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AbstractOptical amplification, crucial for modern communication, primarily relies on erbium-doped fibre amplifiers (EDFAs)1,2. Yet, EDFAs only cover a portion of the low-loss spectrum of optical fibres. This has motivated the development of amplifiers operating beyond the erbium gain window. Pioneering work on optical parametric amplifiers (OPAs)3,4using intrinsic third-order optical nonlinearity has led to demonstrations of increased channel capacity. OPAs offer high gain, can reach the 3-dB quantum limit for phase-preserving amplifiers and exhibit unidirectional operation. However, power requirements for highly nonlinear fibres3,5–8or bulk waveguides9,10have impeded their adoption. By contrast, OPAs based on integrated photonic circuits offer the advantages of substantially increased mode confinement and optical nonlinearity but have been limited in bandwidth11,12. We overcome this challenge by using low-loss gallium phosphide-on-silicon dioxide13–15photonic integrated circuits (PICs) and attain up to 35 dB of parametric gain with waveguides only a few centimetres long in a compact footprint of 0.25 square millimetres. Fibre-to-fibre net gain exceeding 10 dB across an ultra-broad bandwidth of approximately 140 nm (that is, 17 THz) is achieved, with a threefold increase in the gain window compared with C-band EDFAs. We further demonstrate a high dynamic range for input signals, spanning six orders of magnitude, while maintaining a low noise figure. We exploit these performance characteristics to amplify coherent communication signals. This marks, to our knowledge, the first ultra-broadband, high-gain, continuous-wave amplification in a photonic chip, opening up new capabilities for next-generation integrated photonics.
AbstractAntigenic variation is an immune evasion strategy used by many different pathogens. It involves the periodic, non-random switch in the expression of different antigens throughout an infection. How the observed hierarchy in antigen expression is achieved has remained a mystery1,2. A key challenge in uncovering this process has been the inability to track transcriptome changes and potential genomic rearrangements in individual cells during a switch event. Here we report the establishment of a highly sensitive single-cell RNA sequencing approach for the model protozoan parasiteTrypanosoma brucei. This approach has revealed genomic rearrangements that occur in individual cells during a switch event. Our data show that following a double-strand break in the transcribed antigen-coding gene—an important trigger for antigen switching—the type of repair mechanism and the resultant antigen expression depend on the availability of a homologous repair template in the genome. When such a template was available, repair proceeded through segmental gene conversion, creating new, mosaic antigen-coding genes. Conversely, in the absence of a suitable template, a telomere-adjacent antigen-coding gene from a different part of the genome was activated by break-induced replication. Our results show the critical role of repair sequence availability in the antigen selection mechanism. Furthermore, our study demonstrates the power of highly sensitive single-cell RNA sequencing methods in detecting genomic rearrangements that drive transcriptional changes at the single-cell level.
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AbstractHepatic stellate cells (HSCs) have a central pathogenetic role in the development of liver fibrosis. However, their fibrosis-independent and homeostatic functions remain poorly understood1–5. Here we demonstrate that genetic depletion of HSCs changes WNT activity and zonation of hepatocytes, leading to marked alterations in liver regeneration, cytochrome P450 metabolism and injury. We identify R-spondin 3 (RSPO3), an HSC-enriched modulator of WNT signalling, as responsible for these hepatocyte-regulatory effects of HSCs. HSC-selective deletion ofRspo3phenocopies the effects of HSC depletion on hepatocyte gene expression, zonation, liver size, regeneration and cytochrome P450-mediated detoxification, and exacerbates alcohol-associated and metabolic dysfunction-associated steatotic liver disease.RSPO3expression decreases with HSC activation and is inversely associated with outcomes in patients with alcohol-associated and metabolic dysfunction-associated steatotic liver disease. These protective and hepatocyte-regulating functions of HSCs via RSPO3 resemble the R-spondin-expressing stromal niche in other organs and should be integrated into current therapeutic concepts.
AbstractIn a subset of children and adolescents, SARS-CoV-2 infection induces a severe acute hyperinflammatory shock1termed multisystem inflammatory syndrome in children (MIS-C) at four to eight weeks after infection. MIS-C is characterized by a specific T cell expansion2and systemic hyperinflammation3. The pathogenesis of MIS-C remains largely unknown. Here we show that acute MIS-C is characterized by impaired reactivation of virus-reactive memory T cells, which depends on increased serum levels of the cytokine TGFβ resembling those that occur during severe COVID-19 (refs.4,5). This functional impairment in T cell reactivity is accompanied by the presence of TGFβ-response signatures in T cells, B cells and monocytes along with reduced antigen-presentation capabilities of monocytes, and can be reversed by blocking TGFβ. Furthermore, T cell receptor repertoires of patients with MIS-C exhibit expansion of T cells expressing TCRVβ21.3, resembling Epstein–Barr virus (EBV)-reactive T cell clones capable of eliminating EBV-infected B cells. Additionally, serum TGFβ in patients with MIS-C can trigger EBV reactivation, which is reversible with TGFβ blockade. Clinically, the TGFβ-induced defect in T cell reactivity correlates with a higher EBV seroprevalence in patients with MIS-C compared with age-matched controls, along with the occurrence of EBV reactivation. Our findings establish a connection between SARS-CoV-2 infection and COVID-19 sequelae in children, in which impaired T cell cytotoxicity triggered by TGFβ overproduction leads to EBV reactivation and subsequent hyperinflammation.
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Pelage coloration, which serves numerous functions, is crucial to the evolution of behavior, physiology, and habitat preferences of mammals. However, little is known about the coloration of Mesozoic mammaliaforms that coevolved with dinosaurs. In this study, we used a dataset of melanosome (melanin-containing organelle) morphology and quantitatively measured hair colors from 116 extant mammals to reliably reconstruct the coloration of six Mesozoic mammaliaforms, including a previously undescribed euharamiyidan. Unlike the highly diverse melanosomes discovered in feathered dinosaurs, hairs in six mammaliaforms of different lineages and diverse ecomorphotypes showed uniform melanosome geometry, corresponding to dark-brown coloration consistent with crypsis and nocturnality. Our results suggest that the melanosome variation and color expansion seen in extant mammals may have occurred during their rapid radiation and diversification after the Cretaceous-Paleogene extinction.
Nitrous oxide (N2O) is a potent greenhouse gas and the main stratospheric ozone-depleting agent, yet its sources are not well resolved. In this work, we experimentally show a N2O production pathway not previously considered in greenhouse gas budgets, which we name photochemodenitrification. Sunlight induces substantial and consistent N2O production under oxic abiotic conditions in fresh and marine waters. We measured photochemical N2O production rates using isotope tracers and determined that nitrite is the main substrate and that nitrate can also contribute after being photoreduced to nitrite. Additionally, this N2O production was strongly correlated to the radiation dose. Photochemodenitrification exceeded biological N2O production in surface waters. Although previously overlooked, this process may contribute considerably to global N2O emissions through its occurrence in fresh and marine surface waters.
The flagellum ofTrypanosoma bruceidrives the parasite’s characteristic screw-like motion and is essential for its replication, transmission, and pathogenesis. However, the molecular details of this process remain unclear. Here, we present high-resolution (up to 2.8 angstrom) cryo–electron microscopy structures ofT. bruceiflagellar doublet microtubules (DMTs). Integrated modeling identified 154 different axonemal proteins inside and outside the DMT and, together with genetic and proteomic interrogation, revealed conserved and trypanosome-specific foundations of flagellum assembly and motility. We captured axonemal dynein motors in their pre–power stroke state. Comparing atomic models between pre– and post–power strokes defined how dynein structural changes drive sliding of adjacent DMTs during flagellar beating. This study illuminates structural dynamics underlying flagellar motility and identifies pathogen-specific proteins to consider for therapeutic interventions targeting neglected diseases.
Current organic light-emitting diode (OLED) technology uses light-emitting molecules in a molecular host. We report green circularly polarized luminescence (CPL) in a chirally ordered supramolecular assembly, with 24% dissymmetry in a triazatruxene (TAT) system. We found that TAT assembled into helices with a pitch of six molecules, associating angular momentum to the valence and conduction bands and obtaining the observed CPL. Cosublimation of TAT as the “guest” in a structurally mismatched “host” enabled fabrication of thin films in which chiral crystallization was achieved in situ by thermally triggered nanophase segregation of dopant and host while preserving film integrity. The OLEDs showed external quantum efficiencies of up to 16% and electroluminescence dissymmetries ≥10%. Vacuum deposition of chiral superstructures opens new opportunities to explore chiral-driven optical and transport phenomena.
Antarctic ice shelves buttress the grounded ice sheet, mitigating global sea level rise. However, fundamental mechanical properties, such as the ice flow law and viscosity structure, remain under debate. In this work, by leveraging remote-sensing data and physics-informed deep learning, we provide evidence over several ice shelves that the flow law follows a grain size–sensitive composite rheology in the compression zone. In the extension zone, we found that ice exhibits anisotropic properties. We constructed ice shelf–wide anisotropic viscosity maps that capture the suture zones, which inhibit rift propagation. The inferred stress exponent near the grounding zone dictates the grounding-line ice flux and grounding line stability, whereas the inferred viscosity maps inform the prediction of rifts. Both are essential for predicting the future mass loss of the Antarctic Ice Sheet.
Interstellar dust grains cause extinction (absorption and scattering) of light from background astronomical sources. The spectral shape of the extinction curve depends on the dust composition. We used low-resolution optical spectra to measure the extinction curve of 130 million stars. By inverting these data, we mapped the extinction curve parameterR(V) within the Milky Way in three dimensions and within the Magellanic Clouds in two dimensions. These maps provide improved extinction corrections for astronomical observations. We find thatR(V) varies with extinction, consistent with dust grains growing by accretion in low-extinction regions and by coagulation in higher-extinction regions. Star-forming regions have highR(V) values, indicating either preferential destruction of small dust grains or additional supply of large dust grains in those regions.
Highlights from theSciencefamily of journals
Membrane projections from muscle cells enable signaling in the developing mouse heart
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Rattan palms illuminate the drivers of biodiversity in tropical Asia
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Diet influences macronutrient availability to cells, and although mechanisms of sensing dietary glucose and amino acids are well characterized, less is known about sensing lipids. We defined a nutrient signaling mechanism involving fatty acid–binding protein 5 (FABP5) and mechanistic target of rapamycin complex 1 (mTORC1) that is activated by the essential polyunsaturated fatty acid (PUFA) ω-6 linoleic acid (LA). FABP5 directly bound to the regulatory-associated protein of mTOR (Raptor) to enhance formation of functional mTORC1 and substrate binding, ultimately converging on increased mTOR signaling and proliferation. The amounts of FABP5 protein were increased in tumors and serum from triple-negative compared with those from receptor-positive breast cancer patients, which highlights its potential role as a biomarker that mediates cellular responses to ω-6 LA intake in this disease subtype.
The intestinal immune system must concomitantly tolerate food and commensals and protect against pathogens. Antigen-presenting cells (APCs) orchestrate these immune responses by presenting luminal antigens to CD4+T cells and inducing their differentiation into regulatory (peripheral regulatory T cell) or inflammatory [T helper (Th) cell] subsets. We used a proximity labeling method (LIPSTIC) to identify APCs that presented dietary antigens under tolerizing and inflammatory conditions and to understand cellular mechanisms by which tolerance to food is induced and can be disrupted by infection. Helminth infections disrupted tolerance induction proportionally to the reduction in the ratio between tolerogenic APCs—including migratory dendritic cells (cDC1s) and Rorγt+APCs—and inflammatory APCs, which were primarily cDC2s. These inflammatory cDC2s expanded by helminth infection did not present dietary antigens, thus avoiding diet-specific Th2 responses.
In the developing mammalian heart, the endocardium and the myocardium are separated by so-called cardiac jelly. Communication between the endocardium and the myocardium is essential for cardiac morphogenesis. How membrane-localized receptors and ligands achieve interaction across the cardiac jelly is not understood. Working in developing mouse cardiac morphogenesis models, we used a variety of cellular, imaging, and genetic approaches to elucidate this question. We found that myocardium and endocardium interacted directly through microstructures termed tunneling nanotube–like structures (TNTLs). TNTLs extended from cardiomyocytes (CMs) to contact endocardial cells (ECs) directly. TNTLs transported cytoplasmic proteins, transduced signals between CMs and ECs, and initiated myocardial growth toward the heart lumen to form ventricular trabeculae-like structures. Loss of TNTLs disturbed signaling interactions and, subsequently, ventricular patterning.
Some termination letters cite “biological realities” to dismiss usefulness of such research
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A lipid chaperone enables sensing of an essential fatty acid to drive tumor growth
Expedition finds the virus in 13 bird and seal species around the Antarctic Peninsula
Implications draw on the history of transformative information systems from the past
Floods threaten to spread sediments laden with toxicants
In trio of studies, scientists explore life in the mysterious hadal zone
The use of water as a weapon in highly industrialized areas in the Russo-Ukrainian war has resulted in catastrophic economic and environmental damages. We analyze environmental effects caused by the military destruction of the Kakhovka Dam. We link field, remote sensing, and modeling data to demarcate the disaster’s spatial-temporal scales and outline trends in reestablishment of damaged ecosystems. Although media attention has focused on the immediate impacts of flooding on society, politics, and the economy, our results show that toxic contamination within newly exposed sediments of the former reservoir bed poses a largely overlooked long-term threat to freshwater, estuarine, and marine ecosystems. The continued use of water as a weapon may lead to even greater risks for people and the environment.
A partnership can be demanding, and as with any couple, can have good days and bad. The United States–Canada relationship is most definitely having a bad one. It’s difficult to fully comprehend all the dimensions of the current threats to one of the world’s strongest, longest, and multifaceted alliances. From contemptuous musings on annexation to a tariff war that could wreak economic havoc on both sides of the border, the insults and aggravations are stoking uncertainty about a relationship that has flourished for decades. This includes a strongly intertwined connection between Canadian and American science—one that must continue in these challenging times.
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Distributed across two continents and thousands of islands, the Asian tropics are among the most species-rich areas on Earth. The origins of this diversity, however, remain poorly understood. Here, we reveal and classify contributions of individual tropical Asian regions to their overall diversity by leveraging species-level phylogenomic data and new fossils from the most species-rich Asian palm lineage, the rattans and relatives (Arecaceae, Calamoideae). Radiators (Borneo) generate and distribute diversity, incubators (Indochina, New Guinea, and Sulawesi) produce diversity in isolation, corridors (Java, Maluku, Sumatra, and the Thai-Malay Peninsula) connect neighboring regions, and accumulators (Australia, India, Palawan, and the Philippines) acquire diversity generated elsewhere. These contrasting contributions can be explained by differences in region size and isolation, elucidating how the unique island-dominated geography of the Asian tropics drives their outstanding biodiversity.
Although the global economy requires geological resource mining, production has substantial environmental impacts, including the use of regional available water. In this study, we shed light on the global production capacity of 32 mined geological resources, considering regional water availability as a constraint. We found that current resource mining greatly exceeds regional water constraints for several, notably copper (37% of current production exceeds available water capacity) in 2010. Changing the location of production to regions of lower water stress would alleviate current exceedances of water constraints; however, considering economic factors shows that this is not always feasible. Future demand for geological resources is expected to require a considerable increase in water consumption. Considering the constraints of water resources in geological resource production is crucial for sustainability.
At least 1.1 million years old, a fossil face suggests more than one type of early human inhabited Europe
RFK Jr. has claimed conflicts of interest must be rooted out of key CDC panel
Cochlear implants give deaf kids unprecedented access to sound. But insisting they avoid using sign language may be risky
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AbstractThe Human BioMolecular Atlas Program (HuBMAP) aims to construct a 3D Human Reference Atlas (HRA) of the healthy adult body. Experts from 20+ consortia collaborate to develop a Common Coordinate Framework (CCF), knowledge graphs and tools that describe the multiscale structure of the human body (from organs and tissues down to cells, genes and biomarkers) and to use the HRA to characterize changes that occur with aging, disease and other perturbations. HRA v.2.0 covers 4,499 unique anatomical structures, 1,195 cell types and 2,089 biomarkers (such as genes, proteins and lipids) from 33 ASCT+B tables and 65 3D Reference Objects linked to ontologies. New experimental data can be mapped into the HRA using (1) cell type annotation tools (for example, Azimuth), (2) validated antibody panels or (3) by registering tissue data spatially. This paper describes HRA user stories, terminology, data formats, ontology validation, unified analysis workflows, user interfaces, instructional materials, application programming interfaces, flexible hybrid cloud infrastructure and previews atlas usage applications.
AbstractThe availability of single-cell transcriptomics has allowed the construction of reference cell atlases, but their usefulness depends on the quality of dataset integration and the ability to map new samples. Previous benchmarks have compared integration methods and suggest that feature selection improves performance but have not explored how best to select features. Here, we benchmark feature selection methods for single-cell RNA sequencing integration using metrics beyond batch correction and preservation of biological variation to assess query mapping, label transfer and the detection of unseen populations. We reinforce common practice by showing that highly variable feature selection is effective for producing high-quality integrations and provide further guidance on the effect of the number of features selected, batch-aware feature selection, lineage-specific feature selection and integration and the interaction between feature selection and integration models. These results are informative for analysts working on large-scale tissue atlases, using atlases or integrating their own data to tackle specific biological questions.
AbstractThe human genome contains instructions to transcribe more than 200,000 RNAs. However, many RNA transcripts are generated from the same gene, resulting in alternative isoforms that are highly similar and that remain difficult to quantify. To evaluate the ability to study RNA transcript expression, we profiled seven human cell lines with five different RNA-sequencing protocols, including short-read cDNA, Nanopore long-read direct RNA, amplification-free direct cDNA and PCR-amplified cDNA sequencing, and PacBio IsoSeq, with multiple spike-in controls, and additional transcriptome-wideN6-methyladenosine profiling data. We describe differences in read length, coverage, throughput and transcript expression, reporting that long-read RNA sequencing more robustly identifies major isoforms. We illustrate the value of the SG-NEx data to identify alternative isoforms, novel transcripts, fusion transcripts andN6-methyladenosine RNA modifications. Together, the SG-NEx data provide a comprehensive resource enabling the development and benchmarking of computational methods for profiling complex transcriptional events at isoform-level resolution.
AbstractThe Xenium In Situ platform is a new spatial transcriptomics product commercialized by 10x Genomics, capable of mapping hundreds of genes in situ at subcellular resolution. Given the multitude of commercially available spatial transcriptomics technologies, recommendations in choice of platform and analysis guidelines are increasingly important. Herein, we explore 25 Xenium datasets generated from multiple tissues and species, comparing scalability, resolution, data quality, capacities and limitations with eight other spatially resolved transcriptomics technologies and commercial platforms. In addition, we benchmark the performance of multiple open-source computational tools, when applied to Xenium datasets, in tasks including preprocessing, cell segmentation, selection of spatially variable features and domain identification. This study serves as an independent analysis of the performance of Xenium, and provides best practices and recommendations for analysis of such datasets.
AbstractSpatial transcriptomics (ST) has advanced our understanding of tissue regionalization by enabling the visualization of gene expression within whole-tissue sections, but current approaches remain plagued by the challenge of achieving single-cell resolution without sacrificing whole-genome coverage. Here we present Spotiphy (spot imager with pseudo-single-cell-resolution histology), a computational toolkit that transforms sequencing-based ST data into single-cell-resolved whole-transcriptome images. Spotiphy delivers the most precise cellular proportions in extensive benchmarking evaluations. Spotiphy-derived inferred single-cell profiles reveal astrocyte and disease-associated microglia regional specifications in Alzheimer’s disease and healthy mouse brains. Spotiphy identifies multiple spatial domains and alterations in tumor–tumor microenvironment interactions in human breast ST data. Spotiphy bridges the information gap and enables visualization of cell localization and transcriptomic profiles throughout entire sections, offering highly informative outputs and an innovative spatial analysis pipeline for exploring complex biological systems.
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AbstractRNA velocity exploits the temporal information contained in spliced and unspliced RNA counts to infer transcriptional dynamics. Existing velocity models often rely on coarse biophysical simplifications or numerical approximations to solve the underlying ordinary differential equations (ODEs), which can compromise accuracy in challenging settings, such as complex or weak transcription rate changes across cellular trajectories. Here we present cell2fate, a formulation of RNA velocity based on a linearization of the velocity ODE, which allows solving a biophysically more accurate model in a fully Bayesian fashion. As a result, cell2fate decomposes the RNA velocity solutions into modules, providing a biophysical connection between RNA velocity and statistical dimensionality reduction. We comprehensively benchmark cell2fate in real-world settings, demonstrating enhanced interpretability and power to reconstruct complex dynamics and weak dynamical signals in rare and mature cell types. Finally, we apply cell2fate to the developing human brain, where we spatially map RNA velocity modules onto the tissue architecture, connecting the spatial organization of tissues with temporal dynamics of transcription.
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AbstractCellular organelles undergo constant morphological changes and dynamic interactions that are fundamental to cell homeostasis, stress responses and disease progression. Despite their importance, quantifying organelle morphology and motility remains challenging due to their complex architectures, rapid movements and the technical limitations of existing analysis tools. Here we introduce Nellie, an automated and unbiased pipeline for segmentation, tracking and feature extraction of diverse intracellular structures. Nellie adapts to image metadata and employs hierarchical segmentation to resolve sub-organellar regions, while its radius-adaptive pattern matching enables precise motion tracking. Through a user-friendly Napari-based interface, Nellie enables comprehensive organelle analysis without coding expertise. We demonstrate Nellie’s versatility by unmixing multiple organelles from single-channel data, quantifying mitochondrial responses to ionomycin via graph autoencoders and characterizing endoplasmic reticulum networks across cell types and time points. This tool addresses a critical need in cell biology by providing accessible, automated analysis of organelle dynamics.
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AbstractThe dynamics of neuron populations commonly evolve on low-dimensional manifolds. Thus, we need methods that learn the dynamical processes over neural manifolds to infer interpretable and consistent latent representations. We introduce a representation learning method, MARBLE, which decomposes on-manifold dynamics into local flow fields and maps them into a common latent space using unsupervised geometric deep learning. In simulated nonlinear dynamical systems, recurrent neural networks and experimental single-neuron recordings from primates and rodents, we discover emergent low-dimensional latent representations that parametrize high-dimensional neural dynamics during gain modulation, decision-making and changes in the internal state. These representations are consistent across neural networks and animals, enabling the robust comparison of cognitive computations. Extensive benchmarking demonstrates state-of-the-art within- and across-animal decoding accuracy of MARBLE compared to current representation learning approaches, with minimal user input. Our results suggest that a manifold structure provides a powerful inductive bias to develop decoding algorithms and assimilate data across experiments.
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AbstractAccurate segmentation of objects in microscopy images remains a bottleneck for many researchers despite the number of tools developed for this purpose. Here, we present Segment Anything for Microscopy (μSAM), a tool for segmentation and tracking in multidimensional microscopy data. It is based on Segment Anything, a vision foundation model for image segmentation. We extend it by fine-tuning generalist models for light and electron microscopy that clearly improve segmentation quality for a wide range of imaging conditions. We also implement interactive and automatic segmentation in a napari plugin that can speed up diverse segmentation tasks and provides a unified solution for microscopy annotation across different microscopy modalities. Our work constitutes the application of vision foundation models in microscopy, laying the groundwork for solving image analysis tasks in this domain with a small set of powerful deep learning models.
AbstractGeneralist methods for cellular segmentation have good out-of-the-box performance on a variety of image types; however, existing methods struggle for images that are degraded by noise, blurring or undersampling, all of which are common in microscopy. We focused the development of Cellpose3 on addressing these cases and here we demonstrate substantial out-of-the-box gains in segmentation and image quality for noisy, blurry and undersampled images. Unlike previous approaches that train models to restore pixel values, we trained Cellpose3 to output images that are well segmented by a generalist segmentation model, while maintaining perceptual similarity to the target images. Furthermore, we trained the restoration models on a large, varied collection of datasets, thus ensuring good generalization to user images. We provide these tools as ‘one-click’ buttons inside the graphical interface of Cellpose as well as in the Cellpose API.
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AbstractAll multicellular systems produce and dynamically regulate extracellular matrices (ECMs) that play essential roles in both biochemical and mechanical signaling. Though the spatial arrangement of these extracellular assemblies is critical to their biological functions, visualization of ECM structure is challenging, in part because the biomolecules that compose the ECM are difficult to fluorescently label individually and collectively. Here, we present a cell-impermeable small-molecule fluorophore, termed Rhobo6, that turns on and red shifts upon reversible binding to glycans. Given that most ECM components are densely glycosylated, the dye enables wash-free visualization of ECM, in systems ranging from in vitro substrates to in vivo mouse mammary tumors. Relative to existing techniques, Rhobo6 provides a broad substrate profile, superior tissue penetration, non-perturbative labeling, and negligible photobleaching. This work establishes a straightforward method for imaging the distribution of ECM in live tissues and organisms, lowering barriers for investigation of extracellular biology.
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AbstractAdvances in computational structure prediction will vastly augment the hundreds of thousands of currently available protein complex structures. Translating these into discoveries requires aligning them, which is computationally prohibitive. Foldseek-Multimer computes complex alignments from compatible chain-to-chain alignments, identified by efficiently clustering their superposition vectors. Foldseek-Multimer is 3–4 orders of magnitudes faster than the gold standard, while producing comparable alignments; this allows it to compare billions of complex pairs in 11 h. Foldseek-Multimer is open-source software available at GitHub viahttps://github.com/steineggerlab/foldseek/,https://search.foldseek.com/search/and the BFMD database.
AbstractEndothelial cells (ECs) help maintain the blood–brain barrier but deteriorate in many neurodegenerative disorders. Here we show, using a specialized method to isolate EC and microglial nuclei from postmortem human cortex (92 donors, 50 male and 42 female, aged 20–98 years), that intranuclear cellular indexing of transcriptomes and epitopes enables simultaneous profiling of nuclear proteins and RNA transcripts at a single-nucleus resolution. We identify a disease-associated subset of capillary ECs in Alzheimer’s disease, amyotrophic lateral sclerosis and frontotemporal degeneration. These capillaries exhibit reduced nuclear β-catenin and β-catenin-downstream genes, along with elevated TNF/NF-κB markers. Notably, these transcriptional changes correlate with the loss of nuclear TDP-43, an RNA-binding protein also depleted in neuronal nuclei. TDP-43 disruption in human and mouse ECs replicates these alterations, suggesting that TDP-43 deficiency in ECs is an important factor contributing to blood–brain barrier breakdown in neurodegenerative diseases.
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AbstractDepolarization of axons is necessary for somatic action potentials to trigger axonal neurotransmitter release. Here we show that striatal cholinergic interneurons (ChIs) and nicotinic receptors (nAChRs) on mouse dopamine axons interrupt this relationship. After nAChR-mediated depolarization, dopamine release by subsequent depolarization events was suppressed for ~100 ms. This suppression was not due to depletion of dopamine or acetylcholine, but to a limited reactivation of dopamine axons after nAChR-mediated depolarization, and is more prominent in dorsal than in ventral striatum. In vivo, nAChRs predominantly depressed dopamine release, as nAChR antagonism in dorsal striatum elevated dopamine detected with optic-fiber photometry of dopamine sensor GRABDA2mand promoted conditioned place preference. Our findings reveal that ChIs acting via nAChRs transiently limit the reactivation of dopamine axons for subsequent action potentials in dopamine neurons and therefore generate a dynamic inverse scaling of dopamine release according to ChI activity.
AbstractRecent studies suggest the existence of brain-first and body-first subtypes within the Lewy body disorder (LBD) spectrum, including Parkinson’s disease. These studies primarily focused on α-synuclein propagation through the parasympathetic vagal and olfactory bulb routes, leaving the possibility of a sympathetic nervous system spreading route unexplored. In the present study, we analyzed two postmortem datasets, which included 173 and 129 cases positive for Lewy pathology. We observed a clear distinction between brain-first and body-first subtypes in early prediagnostic cases with mild Lewy pathology. Brain-first cases displayed minimal peripheral organ pathology in prediagnostic phases, contrasting with marked autonomic involvement in prediagnostic body-first cases. Utilizing the SuStaIn machine learning algorithm, we identified two distinct body-first subtypes, one with vagal predominance and another with sympathetic predominance, in equal proportions. Our study supports the existence of three prediagnostic LBD subtypes and highlights the sympathetic nervous system alongside the parasympathetic system in LBD onset and progression.
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AbstractThe hippocampus is critical for memory, imagination and constructive reasoning. Recent models have suggested that its neuronal responses can be well explained by state spaces that model the transitions between experiences. Here we use simulations and hippocampal recordings to reconcile these views. We show that if state spaces are constructed compositionally from existing building blocks, or primitives, hippocampal responses can be interpreted as compositional memories, binding these primitives together. Critically, this enables agents to behave optimally in new environments with no new learning, inferring behavior directly from the composition. We predict a role for hippocampal replay in building and consolidating these compositional memories. We test these predictions in two datasets by showing that replay events from newly discovered landmarks induce and strengthen new remote firing fields. When the landmark is moved, replay builds a new firing field at the same vector to the new location. Together, these findings provide a framework for reasoning about compositional memories and demonstrate that such memories are formed in hippocampal replay.
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AbstractHere we report a conserved transcriptomic signature of reduced fatty acid and lipid metabolism gene expression in aDrosophilamodel ofC9orf72repeat expansion, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), and in human postmortem ALS spinal cord. We performed lipidomics on C9 ALS/FTDDrosophila, induced pluripotent stem (iPS) cell neurons and postmortem FTD brain tissue. This revealed a common and specific reduction in phospholipid species containing polyunsaturated fatty acids (PUFAs). Feeding C9 ALS/FTD flies PUFAs yielded a modest increase in survival. However, increasing PUFA levels specifically in neurons of C9 ALS/FTD flies, by overexpressing fatty acid desaturase enzymes, led to a substantial extension of lifespan. Neuronal overexpression of fatty acid desaturases also suppressed stressor-induced neuronal death in iPS cell neurons of patients with both C9 and TDP-43 ALS/FTD. These data implicate neuronal fatty acid saturation in the pathogenesis of ALS/FTD and suggest that interventions to increase neuronal PUFA levels may be beneficial.
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AbstractWe offer a novel motivational account of romantic love, which portrays it as a means to the end of feeling significant and worthy. According to the model, falling in love with a partner depends on the actor's perceptions that (1) the partner possesses meritorious characteristics, and (2) that they appreciate the actor and view them as significant. We assume that these two factors multiplicatively combine with the magnitude of actor's quest for significance to determine the likelihood of actor becoming enamored with partner. The multiplicative model has two major implications: 1. If any one of the partner'smerit,appreciation, or actor'ssignificance questfactors falls below its respective threshold of acceptability (such that it is subjectively non-existent), the likelihood of falling in love will be negligible. 2. Above their acceptability thresholds, levels of (partner's)merit,appreciationand (actor's)significance questfactors compensate for one another. A partner's lower standing on merit or appreciation is compensated in its impact on falling in love by the partner's higher standing on the remaining dimension. Furthermore, lower levels of either or both of these factors are compensated for by the actor's higher level of significance quest.Our model affords a broad account of diverse love phenomena, allows the derivation of several specific hypotheses supported by prior close-relations research as well as new data, and it offers novel avenues for further research on classic issues in romantic love. The discussion considers our model's unique implications and examines its relation to other theories of love.
AbstractMany motivational constructs are opaque “black boxes,” and should be replaced by an explicit account of the underlying psychological mechanisms. The theory of motivational systems has begun to provide such an account. I recently contributed to this tradition with a general architecture of motivation, which connects “energization” and “direction” through the goal-setting activity of emotions, and serves as an evolutionary grounded map of motivational processes.
AbstractWhole Trait Theory (and other dynamic theories of personality) can illuminate the process by which motivational states become traits. Mental computational processes constitute part of the explanatory mechanisms that drive trait manifestations. Empirical work on Whole Trait Theory may inform future research directions on mental computational processes.
AbstractSome constructs in motivation science are certainly underdeveloped and some motivation researchers may work with underspecified constructs, as suggested by Murayama and Jach (M&J). However, this is not indicative of a general problem in motivation science. Many motivation theories focus on specific mechanisms underlying motivated behavior and thus have already adopted the computational process perspective that M&J call for.
AbstractMurayama and Jach argue that it is not clearly specified how motivation constructs produce behavior and that this black box should be unpacked. We argue that the authors overlook important classic theory and highlight recent research programs that already started unboxing. We feel that without relying on the mechanisms that such programs uncover, the proposed computational approach will be fruitless.
AbstractShared intentionality is the derived hominin motivation and skills to align mental states. Research on the role of interdependence in the phylogeny of shared intentionality has only considered the archeological record ofHomo heidelbergensis. But ethnographic and fossil data must be considered, too. Doing so suggests that shared intentionality may have been favored inHomo erectusto support persistence hunting.
AbstractInnovations, such as symbolic artifacts, are a product of cognitive abilities but also of cultural context. Factors that may determine the emergence and retention of an innovation include the population's pre-existing cultural repertoire, exposure to relevant ways of thinking, and the invention's utility. Thus, we suggest that the production of symbolic artifacts is not guaranteed even in cognitively advanced societies.
AbstractUsing modern hunter-gatherers to infer about earlyHomo sapiensonly works if at least (a) modern hunter-gatherers represent an unbiased sample of humanity, and (b) modern hunter-gatherers act in ways similar to the behavior of earlyHomo sapiens. Both of these are false, leading to the problem of whether we can draw conclusions about earlyHomo sapiensfrom modern hunter-gatherers.
AbstractWe comment on the consequences of the target article for language evolution research. We propose that the default assumption should be that of language-readiness in extinct hominins, and the integration of different types of available evidence from multiple disciplines should be used to assess the likely extent of the realization of this readiness. The role of archaeological evidence should be reconsidered.
AbstractStibbard-Hawkes' taphonomic findings are valuable, and his call for caution warranted, but the hazards he raises are being mitigated by a multi-pronged approach; current research on behavioural/cognitive modernity is not based solely on material chronology. Theories synthesize data from archaeology, anthropology, psychology, neuroscience, and genetics, and predictions arising from these theories are tested with mathematical and agent-based models.
AbstractThere are indeed questionable motivation constructs in psychology. The diagnosis and proposed remedies in the target article both neglect the crucial consideration that all tendencies to behaviour compete for the same finite set of degrees of freedom. Action selection also has irreducibly economic aspects which should constrain motivation constructs and already inform healthy research programmes.
AbstractThough we see the potential for benefits from the development of process-oriented approaches, we argue that it falls prey to many of the same critiques raised about the existing construct level of analysis. The construct-level approach will likely dominate motivation research until we develop computational models that are not only accurate, but also broadly usable.
AbstractI argue that Murayama and Jach's claim that higher-order motivational constructs face the “black-box” problem is misconceived because it doesn't clearly distinguish between personal and subpersonal explanations. To solve it they propose interpreting motivations as causal effects of mental computational processes. I suggest that their solution might be more compellingly presented as providing a fictionalist perspective on some personal-level constructs.
AbstractMurayama and Jach raise a key problem in behavioral sciences, to which we suggest evolutionary science can provide a solution. We emphasize the role of adaptive mechanisms in shaping behavior and argue for the integration of hierarchical theories of goal-directed cognition and behavioral flexibility, in order to unravel the motivations behind actions that, in themselves, seem disconnected from adaptive goals.
AbstractThe article provides an important warning but its general conclusions should be nuanced: (i) When there is no evidence for it, we should depart from the hypothesis that a species lacks a particular cognitive capacity, and (ii) inferences from absence of evidence can be epistemically sound and scientifically strategic in cognitive and linguistic archaeology.
AbstractThe absence of symbolic material cultural objects in the archaeological record does not prove absence of symbolic cognition. Sometimes perishable materials are selected for symbolic roles, for practical concerns or to indicate a temporary condition. Also some symbolic functions may predate the use of durable materials. Finally, child play and artisan experimentations usually involve cheap and perishable materials. These are symbolic and representational activities that do not leave a material trace.
AbstractStibbard-Hawkes challenges the link between symbolic material evidence and behavioural modernity. Extending this to non-human species, we find that personal adornment, decoration, figurative art, and musical instruments may not uniquely distinguish human cognition. These common criteria may ineffectively distinguish symbolic from non-symbolic cognition or symbolic cognition is not uniquely human. It highlights the need for broader comparative perspectives.
AbstractMetacognitive feelings are an integral part of mental computational processes and influence the outcome of computations. We review supporting evidence on affect inherent in perceptual processes, fluency in study decisions, metacognitive feelings in aha-experiences and intuition, and affect in early phases of interest development. These findings connect to recent theories that combine metacognitive feelings with computational models.
AbstractIntegrating the predictive processing framework into our understanding of motivation offers promising avenues for theoretical development, while shedding light on the computational processes underlying motivated behavior. Here we decompose expected free energy into intrinsic value (i.e., epistemic affordance) and extrinsic value (i.e., instrumental affordance) to provide insights into how individuals adapt to and interact with their environment.
AbstractMurayama and Jach critically evaluate the idea that motivation is a dynamic that determines behavior and propose alternatively that it might be an emergent property that people construe through perceived regularities in experience and action. The critique has value but fails to appreciate the progress that has been made in moving beyond the idea of which the authors are critical.
AbstractMurayama and Jach offer a thoughtful and timely critique of motivation constructs. We largely concur with their basic premises, but offer additional input and clarification regarding the importance of carefully considering the energization and direction components of motivation, and fully attending to the hierarchical aspect of motivation rather than prioritizing particular levels of analysis.
AbstractIn their article, Murayama and Jach contend that a mental computational model demonstrates that high-level motivations are emergent properties from underlying cognitive processes rather than instigators of behaviors. Despite points of agreement with the authors' critiques of the motivation literature, I argue that their claim of dismantling the black box of the human mind has been constructed on shaking grounds.
AbstractAlthough in basic agreement with Murayama and Jach's call for greater attention to the black boxes underlying motivated behavior, we provide examples of our published suggestions regarding how subjective task value (and ability self-concepts) “gets into people's knowledge structures.” We suggest additional mental computational processes to investigate and call for a developmental and situated individual differences approach to this work.
AbstractStibbard-Hawkes's detailed demonstration that in the case of hunter-gatherer artifacts, absence of evidence is not evidence of absence must never be forgotten. The belief that there is a single coherent “human cognitive capacity” difference between modern humans and some unspecified earlier form should be rigorously re-examined.
AbstractSports, team games, and physical skill competitions appear to be a human universal and may have been prevalent throughout the hominin lineage. These activities are cognitively complex and can be associated with a distinctive and symbolic material culture. Yet, many of the artifacts used by foraging groups for sports, team games, and athletic competitions often have a low preservation probability.
AbstractWhile we are sympathetic with Stibbard-Hawkes’ approach, we disagree with the proposal to switch to a “cognitively modern” null for allHomospecies. We argue in favor of a more evidence-driven approach, inspired by recent debates in comparative cognition. Ultimately, parsing the contributions of different genetic and extra-genetic factors in human evolution is more promising than setting a priori nulls.
AbstractModern humans don't always leave cultural or technological evidence. Yet, Mbuti artifacts, like net-hunting tools and patterns, reveal their modern cognitive capacity. They create geometric and musical structures requiring specific working memory seen in modernHomo sapiens. Evidence from Blombos Cave suggests these skills existed 75,000 years ago, underscoring shared cognitive abilities among all modern human populations.
AbstractWe welcome Stibbard-Hawkes's empirical contributions and discussion of interpretive challenges for archaeology, but question some of his characterizations and conclusions. Moving beyond critique, it is time to develop new research methods that eschew simplistic modern/premodern binaries. We advocate an inductive, probabilistic approach using multiple lines of evidence to infer the causes and consequences of behavioral variability across time and space.
AbstractOur species' behavioral and cognitive evolution constitute a key research topic across many scientific disciplines. Based on ethnographic hunter-gatherer data, Stibbard-Hawkes challenges the common link made between past material culture and cognitive capacities. Despite this adequate criticism, archaeology must retain a central role for studying these issues due to its unique access to relevant empirical evidence in deep time.
AbstractI expand Stibbard-Hawkes' exploration of symbolism and cognition to suggest that we also ought to reconsider the strength of connections between cognition and technological complexity. Using early weaponry as a case study I suggest that complexity may be “hidden” in early tools, and further highlight that assessments of technologies as linear and progressive have roots in Western colonial thought.
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AbstractCells secrete a large variety of extracellular vesicles (EVs) to engage in cell-to-cell and cell-to-environment intercellular communication. EVs are functionally involved in many physiological and pathological processes by interacting with cells that facilitate transfer of proteins, lipids and genetic information. However, our knowledge of EVs is incomplete. Here we show that cells actively release exceptionally large (up to 20 µm) membrane-enclosed vesicles that exhibit active blebbing behavior, and we, therefore, have termed them blebbisomes. Blebbisomes contain an array of cellular organelles that include functional mitochondria and multivesicular endosomes, yet lack a definable nucleus. We show that blebbisomes can both secrete and internalize exosomes and microvesicles. Blebbisomes are released from normal and cancer cells, can be observed by direct imaging of cancer cells in vivo and are present in normal bone marrow. We demonstrate that cancer-derived blebbisomes contain a plethora of inhibitory immune checkpoint proteins, including PD-L1, PD-L2, B7-H3, VISTA, PVR and HLA-E. These data identify a very large, organelle-containing functional EV that act as cell-autonomous mobile communication centres capable of integrating and responding to signals in the extracellular environment.
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AbstractTissue patterning coordinates morphogenesis, cell dynamics and fate specification. Understanding how precision in patterning is robustly achieved despite inherent developmental variability during mammalian embryogenesis remains a challenge. Here, based on cell dynamics quantification and simulation, we show how salt-and-pepper epiblast and primitive endoderm (PrE) cells pattern the inner cell mass of mouse blastocysts. Coupling cell fate and dynamics, PrE cells form apical polarity-dependent actin protrusions required for RAC1-dependent migration towards the surface of the fluid cavity, where PrE cells are trapped due to decreased tension. Concomitantly, PrE cells deposit an extracellular matrix gradient, presumably breaking the tissue-level symmetry and collectively guiding their own migration. Tissue size perturbations of mouse embryos and their comparison with monkey and human blastocysts further demonstrate that the fixed proportion of PrE/epiblast cells is optimal with respect to embryo size and tissue geometry and, despite variability, ensures patterning robustness during early mammalian development.
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AbstractDuring early embryogenesis, fast mitotic cycles without interphase lead to a decrease in cell size, while scaling mechanisms must keep cellular structures proportional to cell size. For instance, as cells become smaller, if the position of nuclear envelope reformation (NER) did not adapt, NER would have to occur beyond the cell boundary. Here we found that NER position in anaphase scales with cell size via changes in chromosome motility, mediated by cytoplasmic flows that themselves scale with cell size. Flows are a consequence of friction between viscous cytoplasm and bulky cargo transported by dynein on astral microtubules. As an emerging property, confinement in cells of different sizes yields scaling of cytoplasmic flows. Thus, flows behave like a cell geometry sensor: astral microtubules approach the boundary causing flow velocity changes, which then affect the velocity of chromosome separation, thus scaling NER.
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AbstractLocalization of mRNAs to neuronal terminals, coupled to local translation, has emerged as a prevalent mechanism controlling the synaptic proteome. However, the physiological regulation and function of this process in the context of mature in vivo memory circuits has remained unclear. Here, we combined synaptosome RNA profiling with whole brain high-resolution imaging to uncover mRNAs with different localization patterns in the axons ofDrosophilaMushroom Body memory neurons, some exhibiting regionalized, input-dependent, recruitment along axons. By integrating transcriptome-wide binding approaches and functional assays, we show that the conserved Imp RNA binding protein controls the transport of mRNAs to Mushroom Body axons and characterize a mutant in which this transport is selectively impaired. Using this unique mutant, we demonstrate that axonal mRNA localization is required for long-term, but not short-term, behavioral memory. This work uncovers circuit-dependent mRNA targeting in vivo and demonstrates the importance of local RNA regulation in memory consolidation.
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AbstractMotor disability is a critical impairment in stroke patients. Rehabilitation has a limited effect on recovery; but there is no medical therapy for post-stroke recovery. The biological mechanisms of rehabilitation in the brain remain unknown. Here, using a photothrombotic stroke model in male mice, we demonstrate that rehabilitation after stroke selectively enhances synapse formation in presynaptic parvalbumin interneurons and postsynaptic neurons in the rostral forelimb motor area with axonal projections to the caudal forelimb motor area where stroke was induced (stroke-projecting neuron). Rehabilitation improves motor performance and neuronal functional connectivity, while inhibition of stroke-projecting neurons diminishes motor recovery. Stroke-projecting neurons show decreased dendritic spine density, reduced external synaptic inputs, and a lower proportion of parvalbumin synapse in the total GABAergic input. Parvalbumin interneurons regulate neuronal functional connectivity, and their activation during training is necessary for recovery. Furthermore, gamma oscillation, a parvalbumin-regulated rhythm, is increased with rehabilitation-induced recovery in animals after stroke and stroke patients. Pharmacological enhancement of parvalbumin interneuron function improves motor recovery after stroke, reproducing rehabilitation recovery. These findings identify brain circuits that mediate rehabilitation-recovery and the possibility for rational selection of pharmacological agents to deliver the first molecular-rehabilitation therapeutic.
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AbstractHow arthritic synovial fibroblasts (SFs) activate cartilage ECM degradation remains unclear. GALNT enzymes initiate O-glycosylation in the Golgi; when relocated to the ER, their activity stimulates ECM degradation. Here, we show that in human rheumatoid and osteoarthritic synovial SFs, GALNTs are relocated to the ER. In an RA mouse model, GALNTs relocation occurs shortly before arthritis symptoms and abates as the animal recovers. An ER GALNTs inhibitor prevents cartilage ECM degradation in vitro and expression of this chimeric protein in SFs results in the protection of cartilage. One of the ER targets of GALNTs is the resident protein Calnexin, which is exported to the cell surface of arthritic SFs. Calnexin participates in matrix degradation by reducing ECM disulfide bonds. Anti-Calnexin antibodies block ECM degradation and protect animals from RA. In sum, ER O-glycosylation is a key switch in arthritic SFs and glycosylated surface Calnexin could be a therapeutic target.
AbstractPrecision medicine requires accurate identification of clinically relevant patient subgroups. Electronic health records provide major opportunities for leveraging machine learning approaches to uncover novel patient subgroups. However, many existing approaches fail to adequately capture complex interactions between diagnosis trajectories and disease-relevant risk events, leading to subgroups that can still display great heterogeneity in event risk and underlying molecular mechanisms. To address this challenge, we implemented VaDeSC-EHR, a transformer-based variational autoencoder for clustering longitudinal survival data as extracted from electronic health records. We show that VaDeSC-EHR outperforms baseline methods on both synthetic and real-world benchmark datasets with known ground-truth cluster labels. In an application to Crohn’s disease, VaDeSC-EHR successfully identifies four distinct subgroups with divergent diagnosis trajectories and risk profiles, revealing clinically and genetically relevant factors in Crohn’s disease. Our results show that VaDeSC-EHR can be a powerful tool for discovering novel patient subgroups in the development of precision medicine approaches.
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AbstractThe initial setting of telomere length during early life in each individual has a major influence on lifetime risk of aging-associated diseases; however there is limited knowledge of biological signals that regulate inheritance of telomere length, and whether it is modifiable is not known. We now show that when mitochondrial activity is disrupted in mouse zygotes, via exposure to 20% O2or rotenone, telomere elongation between the 8-cell and blastocyst stage is impaired, with shorter telomeres apparent in the pluripotent Inner Cell Mass (ICM) and persisting after organogenesis. Identical defects of elevated mtROS in zygotes followed by impaired telomere elongation, occurred with maternal obesity or advanced age. We further demonstrate that telomere elongation during ICM formation is controlled by mitochondrial-nuclear communication at fertilization. Using mitochondrially-targeted therapeutics (BGP-15, MitoQ, SS-31, metformin) we demonstrate that it is possible to modulate the preimplantation telomere resetting process and restore deficiencies in neonatal telomere length.
AbstractPhotonic interconnects between quantum processing nodes are likely the only way to achieve large-scale quantum computers and networks. The bottleneck in such an architecture is the interface between well-isolated quantum memories and flying photons. We establish high-fidelity entanglement between remotely separated trapped atomic qubit memories, mediated by photonic qubits stored in the timing of their pulses. Such time-bin encoding removes sensitivity to polarization errors, enables long-distance quantum communication, and is extensible to quantum memories with more than two states. Using a measurement-based error detection process and suppressing a fundamental source of error due to atomic recoil, we achieve an entanglement fidelity of 97% and show that fundamental limits due to atomic recoil still allow fidelities in excess of 99.9%.
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AbstractRecurrent gain-of-function mutations in the histone reader protein ENL have been identified in Wilms tumor, the most prevalent pediatric kidney cancer. However, their pathological significance in kidney development and tumorigenesis in vivo remains elusive. Here, we generate mouse models mimicking ENL tumor (ENLT) mutations and show that heterozygous mutant expression inSix2+nephrogenic orFoxd1+stromal lineages leads to severe, lineage-specific kidney defects, both resulting in neonatal lethality. Six2-ENLTmutant kidneys display compromised cap mesenchyme, scant nephron tubules, and cystic glomeruli, indicative of premature progenitor commitment and blocked differentiation. Bulk and spatial transcriptomic analyses reveal aberrant activation ofHoxand Wnt signaling genes in mutant nephrogenic cells. In contrast, Foxd1-ENLTmutant kidneys exhibit expansion in renal capsule and cap mesenchyme, with dysregulated stromal gene expression affecting stroma-epithelium crosstalk. Our findings uncover distinct pathways through which ENL mutations disrupt nephrogenesis, providing a foundation for further investigations into their role in tumorigenesis.
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AbstractEarly life stress (ELS) can increase vulnerability to psychiatric disorders, but also trigger resilience. FKBP51 has been associated with an increased risk for developing psychiatric disorders, specifically in interaction with ELS exposure. Here, the contribution of FKBP51 in glutamatergic forebrain neurons to the long-term consequences of ELS was investigated in both sexes. In female wild-typeFkbp5lox/loxmice, ELS exposure led to an anxiolytic phenotype and improved memory performance in a stressful context, however this ELS effect was absent inFkbp5Nexmice. These interactive FKBP51 x ELS effects in female mice were also reflected in reduced brain region volumes, and on structural and electrophysiological properties of CA1 pyramidal neurons of the dorsal hippocampus. In contrast, the behavioral, structural and functional effects in male ELS mice were less pronounced and independent of FKBP51. RNA sequencing of the hippocampus revealed the transcription factor 4 (TCF4) as a potential regulator of the female interactive effects. Cre-dependent viral overexpression of TCF4 in female Nex-Cre mice led to similar beneficial effects on behavior as the ELS exposure. This study demonstrates a sex-specific role for FKBP51 in mediating the adaptive effects of ELS on emotional regulation, cognition, and neuronal function, implicating TCF4 as a downstream effector.
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AbstractThe goals of the current study were to determine the efficacy in major depressive disorder (MDD) of a shortened, computer-augmented cognitive behavioral therapy (CCBT) protocol and to determine brain plasticity effects following CCBT. Seventy-two MDD participants were randomized to CCBT or waitlist control groups and compared to 40 healthy controls (HCs). Functional MRI data were collected for all participants and repeated for patients following CCBT (five therapist-administered manualized CBT sessions plus computer training exercises). Linear mixed-effects models evaluated changes in depression scores throughout treatment and in connectivity from pre- to post-CCBT. Linear regression models compared connectivity differences between groups (MDD vs. HC). Following CCBT, there were decreases in MADRS and BDI (ps < 0.001); there was more negative connectivity of dlPFC with sgACC and DMN with sgACC (ps < 0.002); and there was more positive connectivity of FPN with nucleus accumbens, bilateral amygdalae, bilateral hippocampi, and sgACC and of DMN with ventral and dorsal bilateral anterior insulae (ps < 0.01). There were no associations between change in MADRS and change in connectivity; however, there was an association between change in BDI and change in FPN–sgACC connectivity (p= 0.01). A shortened CBT schedule coupled with home computer exercises was associated with decreased depression symptoms and augmented PFC connectivity with multiple subcortical regions. One possible mechanism of the CCBT intervention is modulating PFC connectivity with subcortical regions, influencing top-down control of affective processes dysregulated in MDD.
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AbstractMolecular neuroimaging techniques, like PET and SPECT, offer invaluable insights into the brain’s in-vivo biology and its dysfunction in neuropsychiatric patients. However, the transition of molecular neuroimaging into diagnostics and precision medicine has been limited to a few clinical applications, hindered by issues like practical feasibility, high costs, and high between-subject heterogeneity of neuroimaging measures. In this study, we explore the use of normative modelling (NM) to identify individual patient alterations by describing the physiological variability of molecular functions. NM potentially addresses challenges such as small sample sizes and diverse acquisition protocols typical of molecular neuroimaging studies. We applied NM to two PET radiotracers targeting the dopaminergic system ([11C]-(+)-PHNO and [18F]FDOPA) to create a reference-cohort model of healthy controls. The models were subsequently utilized on different independent cohorts of patients with psychosis in different disease stages and treatment outcomes. Our results showed that patients with psychosis exhibited a higher degree of extreme deviations (~3-fold increase) than controls, although this pattern was heterogeneous, with minimal overlap of extreme deviations topology (max 20%). We also confirmed that striatal [18F]FDOPA signal, when referenced to a normative distribution, can predict treatment response (striatal AUC ROC: 0.77–0.83). In conclusion, our results indicate that normative modelling can be effectively applied to molecular neuroimaging after proper harmonization, enabling insights into disease mechanisms and advancing precision medicine. In addition, the method is valuable in understanding the heterogeneity of patient populations and can contribute to maximising cost efficiency in studies aimed at comparing cases and controls.
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AbstractThe increased prevalence of opioid use disorder (OUD) makes it imperative to disentangle the biological mechanisms contributing to individual differences in OUD vulnerability. OUD shows strong heritability, however genetic variants contributing to vulnerability remain poorly defined. We performed a genome-wide association study using over 850 male and female heterogeneous stock (HS) rats to identify genes underlying behaviors associated with OUD such as nociception, as well as heroin-taking, extinction and seeking behaviors. By using an animal model of OUD, we were able to identify genetic variants associated with distinct OUD behaviors while maintaining a uniform environment, an experimental design not easily achieved in humans. Furthermore, we used a novel non-linear network-based clustering approach to characterize rats based on OUD vulnerability to assess genetic variants associated with OUD susceptibility. Our findings confirm the heritability of several OUD-like behaviors, including OUD susceptibility. Additionally, several genetic variants associated with nociceptive threshold prior to heroin experience, heroin consumption, escalation of intake, and motivation to obtain heroin were identified.Tom1, a microglial component, was implicated for nociception. Several genes involved in dopaminergic signaling, neuroplasticity and substance use disorders, includingBrwd1,Pcp4, Phb1l2andMmp15were implicated for the heroin traits. Additionally, an OUD vulnerable phenotype was associated with genetic variants for consumption and break point, suggesting a specific genetic contribution for OUD-like traits contributing to vulnerability. Together, these findings identify novel genetic markers related to the susceptibility to OUD-relevant behaviors in HS rats.
AbstractRising adolescent suicide rates present a growing unmet need. Childhood trauma (CT) has been associated with altered cortisol dynamics and immune cell glucocorticoid reactivity, yet their additive longer-term contributions to later suicide outcomes are less clear. The current study compared CT scores, resting salivary free cortisol and mononuclear cell gene expression levels of the nuclear receptor, subfamily 3, member 1 (NR3C1) coding the glucocorticoid receptor, and its co-chaperons FKBP prolyl isomerase 5 (FKBP5) and KIT Ligand (KITLG), between a cohort of adolescents presenting with a suicidal crisis requiring hospital treatment, and matched healthy controls. Childhood trauma scores and glucocorticoid measures were significantly altered among suicidal adolescents, and CT scores correlated with mononuclear cell glucocorticoid transcripts. Both CT scores and glucocorticoid measures explained substantial additive portions of the variance in adolescent suicidality. Long-term perturbations in cortisol dynamics and immune cell glucocorticoid response elements denote dysregulated immune stress reactivity, and may possess value in prediction and point to modifiable-risk factors in prevention of clinically significant suicidality during the brittle period of adolescence, years after childhood trauma exposure.
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AbstractGenetic variants linked to autism are thought to change cognition and behaviour by altering the structure and function of the brain. Although a substantial body of literature has identified structural brain differences in autism, it is unknown whether autism-associated common genetic variants are linked to changes in cortical macro- and micro-structure. We investigated this using neuroimaging and genetic data from adults (UK Biobank, N = 31,748) and children (ABCD, N = 4928). Using polygenic scores and genetic correlations we observe a robust negative association between common variants for autism and a magnetic resonance imaging derived phenotype for neurite density (intracellular volume fraction) in the general population. This result is consistent across both children and adults, in both the cortex and in white matter tracts, and confirmed using polygenic scores and genetic correlations. There were no sex differences in this association. Mendelian randomisation analyses provide no evidence for a causal relationship between autism and intracellular volume fraction, although this should be revisited using better powered instruments. Overall, this study provides evidence for shared common variant genetics between autism and cortical neurite density.
AbstractSerotonin-mediated intercellular communication has been implicated in myriad human behaviors and diseases, yet how serotonin communicates and how the communication is regulated remain unclear due to limitations of available monitoring tools. Here, we report a method multiplexing genetically encoded sensor-based imaging and fast-scan cyclic voltammetry, enabling simultaneous recordings of synaptic, perisynaptic, proximate and distal extrasynaptic serotonergic transmission. Employing this method alongside a genetically encoded sensor-based image analysis program (GESIAP), we discovered that heterogeneous firing patterns of serotonergic neurons create various transmission modes in the mouse raphe nucleus and amygdala, encoding information of firing pulse frequency, number, and synchrony using neurotransmitter quantity, releasing synapse count, and synaptic and/or volume transmission. During tonic and low-frequency phasic activities, serotonin is confined within synaptic clefts due to efficient retrieval by perisynaptic transporters, mediating synaptic transmission modes. Conversely, during high-frequency, especially synchronized phasic activities, or when transporter inhibition, serotonin may surpass transporter capacity, and escape synaptic clefts through 1‒3 outlet channels, leading to volume transmission modes. Our results elucidate a mechanism of how channeled synaptic enclosures, synaptic properties, and transporters collaborate to define the coding principles of activity pattern-dependent serotonergic transmission modes.
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AbstractPrediction from polygenic scores may be confounded by sources of passive gene-environment correlation (rGE; e.g. population stratification, assortative mating, and environmentally mediated effects of parental genotype on child phenotype). Using genomic data from 10 000 twin pairs, we asked whether polygenic scores from the most recent externalising genome-wide association study predict conduct problems, ADHD symptomology and callous-unemotional traits, and whether these predictions are biased by rGE. We ran regression models including within-family and between-family polygenic scores, to separate the direct genetic influence on a trait from environmental influences that correlate with genes (indirect genetic effects). Findings suggested that this externalising polygenic score is a good index of direct genetic influence on conduct and ADHD-related symptoms across development, with minimal bias from rGE, although the polygenic score predicted less variance in CU traits. Post-hoc analyses showed some indirect genetic effects acting on a common factor indexing stability of conduct problems across time and contexts.
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AbstractNon-coding RNAs (ncRNAs) have gained significant attention in recent years due to advancements in biotechnology, particularly high-throughput total RNA sequencing. These developments have led to new understandings of non-coding biology, revealing that approximately 80% of non-coding regions in the genome possesses biochemical functionality. Among ncRNAs, circular RNAs (circRNAs), first identified in 1976, have emerged as a prominent research field. CircRNAs are abundant in most human cell types, evolutionary conserved, highly stable, and formed by back-splicing events which generate covalently closed ends. Notably, circRNAs exhibit high expression levels in neural tissue and perform diverse biochemical functions, including acting as molecular sponges for microRNAs, interacting with RNA-binding proteins to regulate their availability and activity, modulating transcription and splicing, and even translating into functional peptides in some cases. Recent advancements in computational and experimental methods have enhanced our ability to identify and validate circRNAs, providing valuable insights into their biological roles. This review focuses on recent developments in circRNA research as they related to neuropsychiatric and neurodegenerative conditions. We also explore their potential applications in clinical diagnostics, therapeutics, and future research directions. CircRNAs remain a relatively underexplored area of non-coding biology, particularly in the context of neurological disorders. However, emerging evidence supports their role as critical players in the etiology and molecular mechanisms of conditions such as schizophrenia, bipolar disorder, major depressive disorder, Alzheimer’s disease, and Parkinson’s disease. These findings suggest that circRNAs may provide a novel framework contributing to the molecular dysfunctions underpinning these complex neurological conditions.
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Glioblastoma (GBM) is the most prevalent malignant brain tumor with poor prognosis. Although chromatin intratumoral heterogeneity is a characteristic feature of GBM, most current studies are conducted at a single tumor site. To investigate the GBM-specific 3D genome organization and its heterogeneity, we conducted Hi-C experiments in 21 GBM samples from nine patients, along with three normal brain samples. We identified genome subcompartmentalization and chromatin interactions specific to GBM, as well as extensive intertumoral and intratumoral heterogeneity at these levels. We identified copy number variants (CNVs) and structural variations (SVs) and demonstrated how they disrupted 3D genome structures. SVs could not only induce enhancer hijacking but also cause the loss of enhancers to the same gene, both of which contributed to gene dysregulation. Our findings provide insights into the GBM-specific 3D genome organization and the intratumoral heterogeneity of this organization and open avenues for understanding this devastating disease.
Lipid homeostasis is critical to neuronal survival. ATP-binding cassette A (ABCA) proteins are lipid transporters associated with neurodegenerative diseases. How ABCA transporters regulate lipid homeostasis in neurodegeneration is an outstanding question. Here we report that theDrosophilaABCA protein engulfment ABC transporter in the ovary (Eato) regulates phagocytosis-dependent neurodegeneration by playing opposing roles in neurons and phagocytes: In neurons, Eato prevents dendrites and axons from being attacked by neighboring phagocytes; in phagocytes, Eato sensitizes the cell for detecting neurons as engulfment targets. Thus,Eatodeficiency in neurons alone causes phagocytosis-dependent neurite degeneration, but additionalEatoloss from phagocytes suppresses the neurite degeneration. Mechanistically, Eato functions by removing the eat-me signal phosphatidylserine from the cell surface in both neurons and phagocytes. Multiple human and worm ABCA homologs can rescueEatoloss in phagocytes but not in neurons, suggesting both conserved and cell type–specific activities of ABCA proteins. These results imply possible mechanisms of neuron-phagocyte interactions in neurodegenerative diseases.
Oxygen plays a critical role in early neural development in brains, particularly before establishment of complete vasculature; however, it has seldom been investigated due to technical limitations. This study uses an in vitro human cerebral organoid model with multiomic analysis, integrating advanced microscopies and single-cell RNA sequencing, to monitor tissue oxygen tension during neural development. Results reveal a key period between weeks 4 and 6 with elevated intra-organoid oxygen tension, altered energy homeostasis, and rapid neurogenesis within the organoids. The timed oxygen tension elevation can be suppressed by hypoxia treatment or silencing of neuroglobin gene. This study provides insights into the role of oxygen in early neurogenesis from functional, genotypic, phenotypic, and proteomic aspects. These findings highlight the significance of the timed tissue oxygen tension elevation in neurogenesis and provide insights into the role of neuroglobin in neural development, with potential implications for understanding neurodegenerative diseases and therapeutic strategies.
Whether restoration actions achieve full ecological recovery is still debated. This is particularly controversial in the marine realm, where the success of restoration is mostly evaluated in terms of the short-term survival of transplanted organisms. In view of this, we combined population and trait-based approaches to explore the long-term effectiveness of active restoration of a key Mediterranean octocoral. For this purpose, an assemblage with restoredCorallium rubrumcolonies was monitored over 10 years and compared with a nearby reference site. Our results revealed growth of the transplanted colonies followed by a change in the functional structure (i.e., dominance and diversity of traits) of the restored assemblage. This change was related not only to the development of the coral but also to the arrival and/or increase of species with different traits. Overall, our findings provide an example of how active restoration of long-lived octocorals can be an effective tool for recovering high-diverse coralligenous assemblages at decadal timescales.
Invasive infections by encapsulated bacteria are the major cause of human morbidity and mortality. The liver resident macrophages, Kupffer cells, form the hepatic firewall to clear many encapsulated bacteria in the blood circulation but fail to control certain high-virulence capsule types. Here we report that the spleen is the backup immune organ to clear the liver-resistant serotypes ofStreptococcus pneumoniae(pneumococcus), a leading human pathogen. Asplenic mice failed to control the growth of the liver-resistant pneumococci in the blood circulation. Immunologic and genetic analyses identified splenic red pulp (RP) macrophages as the major phagocytes for bacterial clearance. Furthermore, the plasma natural antibodies against the cell wall phosphocholine and the complement system were necessary for RP macrophage–mediated immunity. These findings have provided a conceptual framework for the innate defense against blood bacterial infections, a mechanistic explanation for the hyper-susceptibility of asplenic individuals toS. pneumoniae, and a proof of concept for developing vaccines and therapeutic antibodies against encapsulated pathogens.
Tissue stiffness plays a crucial role in regulating morphogenesis. The ability to measure and monitor the dynamic progression of tissue stiffness is important for generating and testing mechanistic hypotheses. Methods to measure tissue properties in vivo have been emerging but present challenges with spatial and temporal resolution especially in 3D, by their reliance on highly specialized equipment, and/or due to their invasive nature. Here, we introduce light sheet elastography, a noninvasive method that couples low-frequency shear waves with light sheet fluorescence microscopy by adapting commercially available instruments. With this method, we achieved in toto stiffness mapping of organ-stage mouse and zebrafish embryos at cellular resolution. Versatility of the method enabled time-lapse stiffness mapping during tissue remodeling and of the beating embryonic heart. This method expands the spectrum of tools available to biologists and presents opportunities for uncovering the mechanical basis of morphogenesis.
Predictions of tropical cyclone (TC) frequencies are hampered by insufficient knowledge of their natural variability in the past. A 30-m-long sediment core from the Great Blue Hole, a marine sinkhole offshore Belize, provides the longest available, continuous, and annually resolved TC-frequency record. This record expands our understanding, derived from instrumental monitoring (73 years), historical documentations (173 years), and paleotempestological records (2000 years), to the past 5700 years. A total of 694 event layers were identified. They display a distinct regional trend of increasing storminess in the southwestern Caribbean, which follows an orbitally driven shift in the Intertropical Convergence Zone. Superimposed short-term variations match Holocene climate intervals and originate from solar irradiance–controlled sea-surface temperature anomalies and climate phenomena modes. A 21st-century extrapolation suggests an unprecedented increase in TC frequency, attributable to the Industrial Age warming.
Aortic valve stenosis (AVS) is a progressive disease, wherein males more often develop valve calcification relative to females that develop valve fibrosis. Valvular interstitial cells (VICs) aberrantly activate to myofibroblasts during AVS, driving the fibrotic valve phenotype in females. Myofibroblasts further differentiate into osteoblast-like cells and produce calcium nanoparticles, driving valve calcification in males. We hypothesized that the lysine demethylase UTY (ubiquitously transcribed tetratricopeptide repeat containing Y-linked) decreases methylation uniquely in male VICs responding to nanoscale extracellular matrix cues to promote an osteoblast-like cell phenotype. Here, we describe a hydrogel biomaterial cell culture platform to interrogate how nanoscale cues modulate sex-specific methylation states in VICs activating to myofibroblasts and osteoblast-like cells. We found that UTY modulates the osteoblast-like cell phenotype in response to nanoscale cues uniquely in male VICs. Overall, we reveal a previously unidentified role of UTY in the regulation of calcification processes in males during AVS progression.
Bacterial populations experience chemical gradients in nature. However, most experimental systems either ignore gradients or fail to capture gradients in mechanically relevant contexts. Here, we use microfluidic experiments and biophysical simulations to explore how host-relevant shear flow affects antimicrobial gradients across communities of the highly resistant pathogenPseudomonas aeruginosa. We discover that flow patterns gradients of three chemically distinct antimicrobials: hydrogen peroxide, gentamicin, and carbenicillin. Without flow, resistantP. aeruginosacells generate local gradients by neutralizing all three antimicrobials through degradation or chemical modification. As flow increases, delivery overwhelms neutralization, allowing antimicrobials to penetrate deeper into bacterial populations. By imaging single cells across long microfluidic channels, we observe that upstream cells protect downstream cells, and protection is abolished in higher flow regimes. Together, our results reveal that physical flow can promote antimicrobial effectiveness, which could inspire the incorporation of flow into the discovery, development, and implementation of antimicrobials.
Intrabronchial delivery of therapeutic agents is critical to the treatment of respiratory diseases. Targeted delivery is demanded because of the off-target accumulation of drugs in normal lung tissues caused by inhalation and the limited motion dexterity of clinical bronchoscopes in tortuous bronchial trees. Herein, we developed microrobotic swarms consisting of magnetic hydrogel microparticles to achieve intrabronchial targeted delivery. Under programmed magnetic fields, the microgel particle swarms performed controllable locomotion and adaptative structure reconfiguration in tortuous and air-filled environments. The swarms were further integrated with imaging contrast agents for precise tracking under x-ray fluoroscopy and computed tomography imaging. Magnetic navigation of the swarms in an ex vivo lung phantom and in vivo delivery into deep branches of the bronchial trees were achieved. The on-demand reconfiguration of swarms for avoiding the microgel particles from entering nontarget bronchi and the precise delivery into tilted bronchi through climbing motion were validated.
Pancreatic cancer (PC) is a highly metastatic malignancy. More than 80% of patients with PC present with advanced-stage disease, preventing potentially curative surgery. The neuropeptide Y (NPY) system, best known for its role in controlling energy homeostasis, has also been shown to promote tumorigenesis in a range of cancer types, but its role in PC has yet to be explored. We show that expression of NPY andNPY1Rare up-regulated in mouse PC models and human patients with PC. Moreover, using the genetically engineered, autochthonous KPR172HC mouse model of PC, we demonstrate that pancreas-specific and whole-body knockout ofNpy1rsignificantly decreases metastasis to the liver. We identify that treatment with the NPY1R antagonist BIBO3304 significantly reduces KPR172HC migratory capacity on cell-derived matrices. Pharmacological NPY1R inhibition in an intrasplenic model of PC metastasis recapitulated the results of our genetic studies, with BIBO3304 significantly decreasing liver metastasis. Together, our results reveal that NPY/NPY1R signaling is a previously unidentified antimetastatic target in PC.
Recalcitrant biofilm infections pose a great challenge to human health. Micro- and nanorobots have been used to eliminate biofilm infections in hard-to-reach regions inside the body. However, applying antibiofilm robots under physiological conditions is limited by the conflicting demands of accessibility and driving force. Here, we introduce a liquid-bodied antibiofilm robot constructed by a dynamically cross-linked magnetic hydrogel. Leveraging the viscoelastic response of the robot enables it to adapt to complex surface topographies such as medical meshes and stents. Upon actuation, the robot can mechanically destroy the biofilm matrix, chemically deactivate bacterial cells, and collect disrupted biofilm debris. The robot’s antibiofilm performance is studied in vitro and demonstrated on a medical mesh and a biliary stent. Tracking and navigation under endoscopy and x-ray imaging in an ex vivo porcine bile duct are demonstrated. Last, in vivo antibiofilm treatment is conducted by indwelling infected stents into mice’s abdominal cavity and clearing the biofilm infection using the proposed robot.
To provide protection, anticipatory T cell–dependent immunity is reliant on the generation and maintenance of a naïve T cell repertoire, which is sufficiently diverse to ensure recognition of newly encountered antigens. Therefore, under steady-state conditions, a given individual needs to maintain a large pool of naïve T cells, ready to respond to potential threats. Here, we demonstrate that N-myc downstream-regulated gene 3 (Ndrg3) is essential for naïve T cell stability. Mice with T cell–specific Ndrg3 loss are lymphopenic, with reduced numbers of conventional T cells and natural killer T cells. We show that in the absence of Ndrg3, naïve CD8+ T cells exhibit high rates of both proliferation and apoptosis, phenotypes that could be partially rescued by transgenic expression of a high-avidity T cell receptor. Furthermore, Ndrg3-deficient cells were refractory to interleukin-4, resulting in reduced Eomes induction, and a decreased virtual memory population. Our study therefore identifies Ndrg3 as an unexpected, pleiotropic regulator of T cell homeostasis.
Anthropogenically forced climate change signals are emerging from the noise of internal variability in observations, and the impacts on society are growing. For decades, Climate or Earth System Models have been predicting how these climate change signals will unfold. While challenges remain, given the growing forced trends and the lengthening observational record, the climate science community is now in a position to confront the signals, as represented by historical trends, in models with observations. This review covers the state of the science on the ability of models to represent historical trends in the climate system. It also outlines robust procedures that should be used when comparing modeled and observed trends and how to move beyond quantification into understanding. Finally, this review discusses cutting-edge methods for identifying sources of discrepancies and the importance of future confrontations.
Lung cancer exhibits altered metabolism, influencing its response to radiation. To investigate the metabolic regulation of radiation response, we conducted a comprehensive, metabolic-wide CRISPR-Cas9 loss-of-function screen using radiation as selection pressure in human non–small cell lung cancer. Lipoylation emerged as a key metabolic target for radiosensitization, with lipoyltransferase 1 (LIPT1) identified as a top hit. LIPT1 covalently conjugates mitochondrial 2-ketoacid dehydrogenases with lipoic acid, facilitating enzymatic functions involved in the tricarboxylic acid cycle. Inhibiting lipoylation, either through genetic LIPT1 knockout or a lipoylation inhibitor (CPI-613), enhanced tumor control by radiation. Mechanistically, lipoylation inhibition increased 2-hydroxyglutarate, leading to H3K9 trimethylation, disrupting TIP60 recruitment and ataxia telangiectasia mutated (ATM)–mediated DNA damage repair signaling, impairing homologous recombination repair. In summary, our findings reveal a critical role of LIPT1 in regulating DNA damage and chromosome stability and may suggest a means to enhance therapeutic outcomes with DNA-damaging agents.
The emergence and rapid spread of multidrug-resistantBotrytis cinereastrains pose a great challenge to the quality and safety of agricultural products and the efficient use of pesticides. Previously unidentified fungicides and targets are urgently needed to combatB. cinerea–associated infections as alternative therapeutic options. In this study, the promising compound Z24 demonstrated efficacy against all tested plant pathogenic fungi. Thiamine thiazole synthase (Bcthi4) was identified as a target protein of Z24 by drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) assays. Molecular docking and enzyme activity experiments have demonstrated that Z24 can affect the function of Bcthi4. Last, mechanistic studies show that Z24 inhibits thiamine biosynthesis by binding to Bcthi4 and induces up-regulation of alternative splicing [alternative 5′ splice site (A5SS)] of theBcthi4gene. In conclusion, by targeting Bcthi4, Z24 has the potential to be developed as a previously unidentified anti–B. cinereacandidate.
There is great interest in using genetically tractable organisms such asDrosophilato gain insights into the regulation and function of sleep. However, sleep phenotyping inDrosophilahas largely relied on simple measures of locomotor inactivity. Here, we present FlyVISTA, a machine learning platform to perform deep phenotyping of sleep in flies. This platform comprises a high-resolution closed-loop video imaging system, coupled with a deep learning network to annotate 35 body parts, and a computational pipeline to extract behaviors from high-dimensional data. FlyVISTA reveals the distinct spatiotemporal dynamics of sleep and wake-associated microbehaviors at baseline, following administration of the sleep-inducing drug gaboxadol, and with dorsal fan-shaped body drivers. We identify a microbehavior (“haltere switch”) exclusively seen during quiescence that indicates a deeper sleep stage. These results enable the rigorous analysis of sleep inDrosophilaand set the stage for computational analyses of microbehaviors in quiescent animals.
After an election, should election officials release a copy of each anonymous ballot? Some policy-makers have championed public disclosure to counter distrust, but others worry that it might undermine ballot secrecy. We introduce the term vote revelation to refer to the linkage of a vote on an anonymous ballot to the voter’s name in the public voter file and detail how such revelation could theoretically occur. Using the 2020 election in Maricopa County, Arizona, as a case study, we show that the release of individual ballot records would lead to no revelation of any vote choice for 99.83% of voters as compared to 99.95% under Maricopa’s current practice of reporting aggregate results by precinct and method of voting. Further, revelation is overwhelmingly concentrated among the few voters who cast provisional ballots or federal-only ballots. We discuss the potential benefits of transparency, compare remedies to reduce or eliminate privacy violations, and highlight the privacy-transparency trade-off inherent in all election reporting.
U6 small nuclear RNA (U6 snRNA), a critical spliceosome component primarily found in the nucleus, plays a vital role in RNA splicing. Our previous study, using the simian immunodeficiency virus (SIV) macaque model, revealed an increase of U6 snRNA in plasma extracellular vesicles (EVs) in acute retroviral infection. Given the limited understanding of U6 snRNA dynamics across cells and EVs, particularly in SIV infection, this research explores U6 snRNA trafficking and its association with splicing proteins in the nucleus, cytoplasm, and EVs. We observed a redistribution of U6 snRNA from the nucleus to EVs post-infection, accompanied by distinct protein profile changes and alterations in nucleic acid metabolism and spliceosome pathways. In addition, U6 machinery proteins changed in cells and EVs in a contrasting manner. The redistribution of U6 and related proteins we observed could be part of a viral strategy to redirect host splicing machinery, suggesting that U6 may have regulatory roles and be part of retroviral infection signature.
The testis-specific BET protein BRDT structurally resembles the ubiquitous BRD4 and is misexpressed in cancer, and we show that BRDT misexpression may affect lung cancer progression. BRDT knockdown in lung cancer cells slowed tumor growth and prolonged survival in a xenograft model. Comparative characterization of PTEFb complex participation and chromatin binding indicates BRD4-redundant and BRD4-distinct BRDT functions. Unlike dual depletion, individual BRD4 or BRDT knockdown did not impair transcriptional responses to hypoxia in BRDT-expressing cells, consistent with redundant function. However, BRD4 depletion/BRDT complementation revealed that BRDT can also release paused RNA polymerase II independently of its bromodomains as we previously demonstrated not to be required for Pol II pause/release function of BRD4, underscoring the functional importance of the C-terminal domains in both BRD4 and BRDT and their potential as therapeutic targets in solid tumors. Based on this study, future investigations should explore BRD4-distinct BRDT functions and BRDT misexpression driving cancer pathogenesis.
Duchenne muscular dystrophy (DMD) is a devastating X-linked disorder caused by dystrophin gene mutations. Despite recent advances in understanding the disease etiology and applying emerging treatment methodologies, glucocorticoid derivatives remain the only general therapeutic option that can slow disease development. However, the precise molecular mechanism of glucocorticoid action remains unclear, and there is still need for additional remedies to complement the treatment. Here, using single-nucleus RNA sequencing and spatial transcriptome analyses of human and mouse muscles, we investigated pathogenic features in patients with DMD and palliative effects of glucocorticoids. Our approach further illuminated the importance of proliferating satellite cells and revealed increased activity of a signal transduction pathway involving EZH2 in the patient cells. Subsequent administration of EZH2 inhibitors toDmdmutant mice resulted in improved muscle phenotype through maintaining the immune-suppressing effect but overriding the muscle weakness and fibrogenic effects exerted by glucocorticoids. Our analysis reveals pathogenic mechanisms that can be readily targeted by extant therapeutic options for DMD.
Timely detection of early atherosclerosis (AS) is crucial for improving cardiovascular outcomes, creating a growing demand for diagnostic tools that are simple, sensitive, and cost-effective. Here, we introduce a synthetic nanosensor for early AS detection that leverages the fluorescence and renal clearance properties of carbon quantum dots (CQDs). This nanosensor, designed to respond to the proteolytic activity of AS-associated dysregulated enzymes, entails CQDs as signal reporters to convert AS-associated proteolytic activity to fluorometric readings enabling a sensitive and cost-effective urine-based assay for early AS detection. Our findings demonstrated that the nanosensor provided distinct signals in atherosclerotic versus healthy mice at early AS stages, indicating its diagnostic potential. Moreover, toxicity tests showed no notable adverse effects, supporting its safety for diagnostic applications. This minimally invasive diagnostic approach could facilitate personalized therapy design and continuous efficacy assessment. It is expected that such a modular nanosensor platform can be integrated with simple urine tests to offer cost-effective detection of various diseases.
Aging involves the progressive accumulation of cellular damage, leading to systemic decline and age-related diseases. Despite advances in medicine, accurately predicting biological age (BA) remains challenging due to the complexity of aging processes and the limitations of current models. This study introduces a method for predicting BA using a deep neural network (DNN) based on pathways of steroidogenesis. We analyzed 22 steroids from 148 serum samples of individuals aged 20 to 73, using 98 samples for model training and 50 for validation. Our model reflects the often-overlooked fact that aging heterogeneity expands over time and uncovers sex-specific variations in steroidogenesis. This study leveraged key markers, including cortisol (COL), which underscore the role of stress-related and sex-specific steroids in aging. The resulting model establishes a biologically meaningful and robust framework for predicting BA across diverse datasets, offering fresh insights and supporting more targeted strategies in aging research and disease management.
In vertebrate Hedgehog (Hh) signaling, the precise output of the final effectors, GLI (glioma-associated oncogene) transcription factors, depends on the primary cilium. Upon pathway initiation, generating the precise levels of the activator form of GLI depends on its concentration at the cilium tip. The mechanisms underlying this critical step in Hh signaling are unclear. We developed an assay to visualize GLI2, the primary GLI activator isoform, at single-particle resolution within the cilium. We found that GLI2 is a cargo of intraflagellar transport (IFT) machinery. Anterograde-biased IFT loading of GLI2 in a restricted time window following pathway activation results in the tip accumulation of GLI2. Unexpectedly, we found that the conserved Hh regulator KIF7, a nonmotile kinesin, is important for the temporal control of IFT-mediated GLI2 transport and retention of GLI2 at the cilium tip. Our findings underscore a design principle where a cilia-specific cytoskeletal transport system and an Hh pathway–specific cytoskeletal protein collaboratively regulate GLI2 trafficking for Hh signaling.
Carbohydrate-responsive element binding protein (ChREBP) and Max-like protein X (MLX) form a heterodimeric transcription factor complex that couples intracellular sugar levels to carbohydrate and lipid metabolism. To promote the expression of target genes, two ChREBP-MLX heterodimers form a heterotetramer to bind a tandem element with two adjacent E-boxes, called carbohydrate-responsive element (ChoRE). How the ChREBP-MLX hetero-tetramerization is achieved and regulated remains poorly understood. Here, we show that MLX phosphorylation on an evolutionarily conserved motif is necessary for the heterotetramer formation on the ChoRE and the transcriptional activity of the ChREBP-MLX complex. We identified casein kinase 2 (CK2) and glycogen synthase kinase 3 (GSK3) as MLX kinases. High intracellular glucose-6-phosphate accumulation inhibits MLX phosphorylation and heterotetramer formation on the ChoRE, impairing ChREBP-MLX activity. Physiologically, MLX phosphorylation is necessary inDrosophilato maintain sugar tolerance and lipid homeostasis. Our findings suggest that MLX phosphorylation is a key mechanism for the ChREBP-MLX heterotetramer formation to regulate carbohydrate and lipid metabolism.
Chromosome 22q11.2 deletion increases the risk of neuropsychiatric disorders like autism and schizophrenia. Disruption of large-scale functional connectivity in 22q11 deletion syndrome (22q11DS) has been widely reported, but the biological factors driving these changes remain unclear. We used a cross-species design to uncover the developmental trajectory and neural underpinnings of brain dysconnectivity in 22q11DS. In LgDel mice, a model for 22q11DS, we found age-specific patterns of brain dysconnectivity, with widespread fMRI hyperconnectivity in juvenile mice reconfiguring to hippocampal hypoconnectivity over puberty. These changes correlated with developmental alterations in dendritic spine density, and both were transiently normalized by GSK3β inhibition, suggesting a synaptic origin for this phenomenon. Notably, analogous pubertal hyperconnectivity-to-hypoconnectivity reconfiguration occurs in human 22q11DS, affecting cortical regions enriched for GSK3β-associated synaptic genes and autism-relevant transcripts. This dysconnectivity also predicts age-dependent social alterations in 22q11DS individuals. These results suggest that synaptic mechanisms underlie developmental brain dysconnectivity in 22q11DS.
The human brain has a remarkable ability to learn and update its beliefs about the world. Here, we investigate how thermosensory learning shapes our subjective experience of temperature and the misperception of pain in response to harmless thermal stimuli. Through computational modeling, we demonstrate that the brain uses a probabilistic predictive coding scheme to update beliefs about temperature changes based on their uncertainty. We find that these expectations directly modulate the perception of pain in the thermal grill illusion. Quantitative microstructural brain imaging further revealed that individual variability in computational parameters related to uncertainty-driven learning and decision-making is reflected in the microstructure of brain regions such as the precuneus, posterior cingulate gyrus, cerebellum, as well as basal ganglia and brainstem. These findings provide a framework to understand how the brain infers pain from innocuous thermal inputs, with important implications for the etiology of thermosensory symptoms under chronic pain conditions.
In positive-strand RNA viruses, the genome serves as a template for both protein translation and negative-strand RNA synthesis. Enteroviruses use the cloverleaf RNA structure at the 5′ end of the genome to balance these two processes. Cloverleaf acts as a promoter for RNA synthesis and forms a complex with viral 3CD protein, the precursor to 3Cproprotease, and 3Dpolpolymerase. The interaction between cloverleaf and 3CD is mediated by the 3Cprodomain, yet how 3Cpropromotes specific RNA-binding is not clear. We report the structure of coxsackievirus cloverleaf RNA-3Cprocomplex, wherein two 3Cpromolecules interact with cloverleaf stem-loop D. 3Cprodimer mainly recognizes the shape of the dsRNA helix through symmetric interactions, suggesting that 3Cprois a previously undiscovered type of RNA binding protein. We show that 3CD protein also dimerizes on cloverleaf RNA and binds the RNA with higher affinity than 3Cpro. The structure provides insight into the RNA-binding mechanism of 3Cproor 3CD with other cis-acting replication elements.
Directed evolution, enzyme design, and effective immobilization have been used to improve the catalytic activity. Dynamic polymers offer a promising platform to improve enzyme activity in aqueous solutions. Here, amphiphilic dynamers and lipase self-assemble into nanoparticles of 150- to 600-nanometer diameter, showing remarkable threefold enhancement in catalytic activity. In addition, they also demonstrated the ability to promote the reversible refolding of the partially or completely denatured lipase. The catalytic efficiency is completed with its more convenient handling of dynameric nanoparticles facilitating the efficient recovery and reuse of the enzyme with cost-effective uses. Molecular simulation studies revealed an in-depth understanding of how the dynamer action mechanism affects the conformational changes of lipase. The dynamer served as an effective hydrophobic support, facilitating the lid opening and substrate access to the catalytic triad, resulting in a substantial activation with an improved stability and recyclability of the lipase.
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Astrocytes, traditionally viewed as supportive cells within the central nervous system (CNS), are now recognized as dynamic regulators of neural signaling and homeostasis. They actively engage in synaptic transmission and brain health by releasing gliotransmitters such as glutamate, GABA, ATP, adenosine, lactate, andd-serine. Astrocytes also play a critical role in ion homeostasis and immune response through cytokine modulation and reactive oxygen species regulation. In pathological states, astrocytes can become reactive, contributing to neurodegeneration through dysregulated gliotransmitter release and metabolic dysfunction. Recently developed molecular and pharmacological tools allow the exploration of astrocytic response to injury and its influence on neuronal function. This review explores the multifaceted roles of astrocytes in health and disease, emphasizing sensory and motor functions as well as various neurological and psychiatric disorders. Understanding astrocyte-neuron signaling in health and disease provides crucial insights into their dual roles, offering novel avenues for therapeutic interventions in CNS disorders.
Life on this planet is heavily influenced by light, the most critical external environmental factor. Mammals perceive environmental light mainly through three types of photoreceptors in the retina—rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs). The latest discovered ipRGCs are particularly sensitive to short-wavelength light and have a unique phototransduction mechanism, compared with rods and cones. Piles of evidence suggest that ipRGCs mediate a series of light-regulated physiological functions such as circadian rhythms, sleep, metabolic homeostasis, mood, development, and higher cognitions, collectively known as non-image-forming vision. Recent advances in systems neuroscience, driven by modern neural circuit tools, have illuminated the structure and function of the neural pathways connecting the retina to subcortical regions, highlighting their involvement in an array of non-image-forming functions. Here we review key discoveries and recent progress regarding the neural circuit mechanisms employed by ipRGCs to regulate diverse biological functions and provide insights into unresolved scientific questions in this area.
Sexually dimorphic instinctual behaviors that set females and males apart are found across animal clades. Recent studies in a variety of animal systems have provided deep insights into the neural circuits that guide sexually dimorphic behaviors, such as mating practices and social responses, and how sex differences in these circuits develop. Here, we discuss the neural circuits of several sexually dimorphic instinctual behaviors in rodents, flies, and worms—from mate attraction and aggression to pain perception and empathy. We highlight several salient similarities and differences between these circuits and reveal general principles that underlie the function and development of neural circuits for dimorphic behaviors.
The formation of new synapses, the connections between neurons, is the critical step for neural circuit assembly. Newly formed glutamatergic synapses are initially silent and require activity-dependent plasticity to become fully functional connections. While these synapses have long been considered a vital part of the developmental program for neural networks, recent findings now indicate that silent synapses are a key source of neural circuit plasticity in the adult brain. Here, we review current evidence for silent synapses in the adult brain and explore the potential roles of these highly plastic structures. We argue that silent synapses may be instrumental in adult neural circuit remodeling and can serve as a latent reservoir of plasticity that enhances information processing and storage. This previously underappreciated aspect of adult plasticity underscores the need for innovative approaches and further investigation into the dynamic contribution of silent synapses to learning and memory in the adult brain.
The synapse is polarized and highly compartmentalized on both its pre- and postsynaptic sides. The compartmentalization of synaptic vesicles, as well as vesicle releasing and recycling machineries, allows neurotransmitters to be released with precisely controlled timing, speed, and amplitude. The compartmentalized and clustered organization of neurotransmitter receptors and their downstream signaling enzymes allows neuronal signals to be properly received and amplified. Synaptic adhesion molecules also form clustered assemblies to align pre- and postsynaptic subcompartments for synaptic formation, stability, and transmission. Recent studies indicate that such synaptic and subsynaptic compartmentalized organizations are formed via phase separation. This review discusses how such condensed subsynaptic compartments may form and function in the context of synapse formation and plasticity. We discuss how phase separation allows for the formation of multiple distinct condensates on both sides of a synapse and how such condensates communicate with each other. We also highlight how proteins display unique properties in condensed phases compared to the same proteins in dilute solutions.
Social behaviors, including parental care, mating, and fighting, all depend on the hormonal milieu of an organism. Decades of work highlighted estrogen as a key hormonal controller of social behaviors, exerting its influence primarily through binding to estrogen receptor alpha (Esr1). Recent technological advances in chemogenetics, optogenetics, gene editing, and transgenic model organisms have allowed for a detailed understanding of the neuronal subpopulations and circuits for estrogen action across Esr1-expressing interconnected brain regions. Focusing on rodent studies, in this review we examine classical and contemporary research demonstrating the multifaceted role of estrogen and Esr1 in regulating social behaviors in a sex-specific and context-dependent manner. We highlight gaps in knowledge, particularly a missing link in the molecular cascade that allows estrogen to exert such a diverse behavioral repertoire through the coordination of gene expression changes. Understanding the molecular and cellular basis of Esr1’s action in social behaviors provides insights into the broader mechanisms of hormone-driven behavior modulation across the lifespan.
During rest and sleep, the brain processes information through replay, reactivating neural patterns linked to past events and facilitating the exploration of potential future scenarios. This review summarizes recent advances in understanding human replay and its biomarker, sharp-wave ripples (SPW-Rs). We explore detection methods and connect insights from rodent studies. The review highlights unique aspects of human replay in internal cognition such as prioritizing past experiences for offline learning, generating hypothesized solutions to current problems, and factorizing structural representations for future generalization. We also examine the characteristics of SPW-Rs in humans, including their distribution along the hippocampal longitudinal axis, their widespread brain activations, and their influence on internal cognitive processes. Finally, we emphasize the need for improved methodologies and technologies to advance our understanding of cognitive processes during rest and sleep.
Major depressive disorder and treatment-resistant depression are significant worldwide health problems that need new therapies. The success of the anesthetic ketamine as an antidepressant is well known. It is less widely known that several other anesthetic agents have also shown antidepressant effects. These include nitrous oxide, propofol, isoflurane, sevoflurane, dexmedetomidine, and xenon. We review clinical and basic science investigations that have studied the therapeutic value of these anesthetics for treating depression. We propose potential neurophysiological mechanisms underlying the antidepressant effects of anesthetics by combining our understanding of how anesthetics modulate brain dynamics to alter arousal states, current theories of depression pathophysiology, and findings from other depression treatment modalities.
Medulloblastoma is the most common pediatric brain cancer and is broadly categorized into four molecular subgroups. Understanding the cell origins of medulloblastoma is crucial for preventing tumor formation and relapse. Recent single-cell transcriptomics studies have identified the potential cell lineage vulnerabilities and mechanisms underpinning malignant transformation in medulloblastoma. Emerging evidence suggests that genetic-epigenetic alterations specific to each subgroup lead to a lineage-specific stall in the neural developmental program and subsequent tumorigenesis. We discuss the putative cells of origin, plasticity, and heterogeneity within medulloblastoma subgroups and delve into the genetic and epigenetic changes that predispose cells to transformation. Additionally, we review the current insights into how cerebellar stem/progenitor cells and lineage plasticity impact medulloblastoma pathogenesis and highlight recent therapeutic advances targeting specific oncogenic vulnerabilities in this malignancy.
Cognition unfolds dynamically over flexible timescales. A major goal of the field is to understand the computational and neurobiological principles that enable this flexibility. Here, we argue that the neurobiology of timing provides a platform for tackling these questions. We begin with an overview of proposed coding schemes for the representation of elapsed time, highlighting their computational properties. We then leverage the one-dimensional and unidirectional nature of time to highlight common principles across these coding schemes. These principles facilitate a precise formulation of questions related to the flexible control, variability, and calibration of neural dynamics. We review recent work that demonstrates how dynamical systems analysis of thalamocortical population activity in timing tasks has provided fundamental insights into how the brain calibrates and flexibly controls neural dynamics. We conclude with speculations about the architectural biases and neural substrates that support the control and calibration of neural dynamics more generally.
Locomotion, like all behaviors, possesses an inherent flexibility that allows for the scaling of movement kinematic features, such as speed and vigor, in response to an ever-changing external world and internal drives. This flexibility is embedded in the organization of the spinal locomotor circuits, which encode and decode commands from the brainstem and proprioceptive feedback. This review highlights our current understanding of the modular organization of these locomotor circuits and how this modularity endows them with intrinsic mechanisms to adjust speed and vigor, thereby contributing to the flexibility of locomotor movements.
The twenty-first century has brought forth a deluge of theories and data shedding light on the neural mechanisms of motivated behavior. Much of this progress has focused on dopaminergic dynamics, including their signaling properties (how do they vary with expectations and outcomes?) and their downstream impacts in target regions (how do they affect learning and behavior?). In parallel, the basal ganglia have been elevated from their original implication in motoric function to a canonical circuit facilitating the initiation, invigoration, and selection of actions across levels of abstraction, from motor to cognitive operations. This review considers how striatal D1 and D2 opponency allows animals to perform cost-benefit calculations across multiple scales: locally, whether to select a given action, and globally, whether to engage a particular corticostriatal circuit for guiding behavior. An emerging understanding of such functions reconciles seemingly conflicting data and has implications for neuroscience, psychology, behavioral economics, and artificial intelligence.
It is a common view that the intricate array of specialized domains in the ventral visual pathway is innately prespecified. What this review postulates is that it is not. We explore the origins of domain specificity, hypothesizing that the adult brain emerges from an interplay between a domain-general map-based architecture, shaped by intrinsic mechanisms, and experience. We argue that the most fundamental innate organization of cortex in general, and not just the visual pathway, is a map-based topography that governs how the environment maps onto the brain, how brain areas interconnect, and ultimately, how the brain processes information.
Deep brain stimulation (DBS), a method in which electrical stimulation is delivered to specific areas of the brain, is an effective treatment for managing symptoms of a number of neurological and neuropsychiatric disorders. Clinical access to neural circuits during DBS provides an opportunity to study the functional link between neural circuits and behavior. This review discusses how the use of DBS in Parkinson's disease and dystonia has provided insights into the brain networks and physiological mechanisms that underlie motor control. In parallel, insights from basic science about how patterns of electrical stimulation impact plasticity and communication within neural circuits are transforming DBS from a therapy for treating symptoms to a therapy for treating circuits, with the goal of training the brain out of its diseased state.
Over 40% of the human genome is composed of retrotransposons, DNA species that hold the potential to replicate via an RNA intermediate and are evolutionarily related to retroviruses. Retrotransposons are most studied for their ability to jump within a genome, which can cause DNA damage and novel insertional mutations. Retrotransposon-encoded products, including viral-like proteins, double-stranded RNAs, and extrachromosomal circular DNAs, can also be potent activators of the innate immune system. A growing body of evidence suggests that retrotransposons are activated in age-related neurodegenerative disorders and that such activation causally contributes to neurotoxicity. Here we provide an overview of retrotransposon biology and outline evidence of retrotransposon activation in age-related neurodegenerative disorders, with an emphasis on those involving TAR-DNA binding protein-43 (TDP-43) and tau. Studies to date provide the basis for ongoing clinical trials and hold promise for innovative strategies to ameliorate the adverse effects of retrotransposon dysregulation in neurodegenerative disorders.
Ant physiology has been fashioned by 100 million years of social evolution. Ants perform many sophisticated social and collective behaviors yet possess nervous systems similar in schematic and scale to that of the fruit fly Drosophila melanogaster, a popular solitary model organism. Ants are thus attractive complementary subjects to investigate adaptations pertaining to complex social behaviors that are absent in flies. Despite research interest in ant behavior and the neurobiological foundations of sociality more broadly, our understanding of the ant nervous system is incomplete. Recent technical advances have enabled cutting-edge investigations of the nervous system in a fashion that is less dependent on model choice, opening the door for mechanistic social insect neuroscience. In this review, we revisit important aspects of what is known about the ant nervous system and behavior, and we look forward to how functional circuit neuroscience in ants will help us understand what distinguishes solitary animals from highly social ones.
The cochlear implant (CI) is considered the most successful neuroprosthesis as it enables speech comprehension in the majority of the million otherwise deaf patients. In hearing by electrical stimulation of the auditory nerve, the broad spread of current from each electrode acts as a bottleneck that limits the transfer of sound frequency information. Hence, there remains a major unmet medical need for improving the quality of hearing with CIs. Recently, optogenetic stimulation of the cochlea has been suggested as an alternative approach for hearing restoration. Cochlear optogenetics promises to transfer more sound frequency information, hence improving hearing, as light can conveniently be confined in space to activate the auditory nerve within smaller tonotopic ranges. In this review, we discuss the latest experimental and technological developments of optogenetic hearing restoration and outline remaining challenges en route to clinical translation.
The zebrafish visual system has become a paradigmatic preparation for behavioral and systems neuroscience. Around 40 types of retinal ganglion cells (RGCs) serve as matched filters for stimulus features, including light, optic flow, prey, and objects on a collision course. RGCs distribute their signals via axon collaterals to 12 retinorecipient areas in forebrain and midbrain. The major visuomotor hub, the optic tectum, harbors nine RGC input layers that combine information on multiple features. The retinotopic map in the tectum is locally adapted to visual scene statistics and visual subfield–specific behavioral demands. Tectal projections to premotor centers are topographically organized according to behavioral commands. The known connectivity in more than 20 processing streams allows us to dissect the cellular basis of elementary perceptual and cognitive functions. Visually evoked responses, such as prey capture or loom avoidance, are controlled by dedicated multistation pathways that—at least in the larva—resemble labeled lines. This architecture serves the neuronal code's purpose of driving adaptive behavior.
The activity patterns of grid cells form distinctively regular triangular lattices over the explored spatial environment and are largely invariant to visual stimuli, animal movement, and environment geometry. These neurons present numerous fascinating challenges to the curious (neuro)scientist: What are the circuit mechanisms responsible for creating spatially periodic activity patterns from the monotonic input-output responses of single neurons? How and why does the brain encode a local, nonperiodic variable—the allocentric position of the animal—with a periodic, nonlocal code? And, are grid cells truly specialized for spatial computations? Otherwise, what is their role in general cognition more broadly? We review efforts in uncovering the mechanisms and functional properties of grid cells, highlighting recent progress in the experimental validation of mechanistic grid cell models, and discuss the coding properties and functional advantages of the grid code as suggested by continuous attractor network models of grid cells.
The cerebral cortex performs computations via numerous six-layer modules. The operational dynamics of these modules were studied primarily in early sensory cortices using bottom-up computation for response selectivity as a model, which has been recently revolutionized by genetic approaches in mice. However, cognitive processes such as recall and imagery require top-down generative computation. The question of whether the layered module operates similarly in top-down generative processing as in bottom-up sensory processing has become testable by advances in the layer identification of recorded neurons in behaving monkeys. This review examines recent advances in laminar signaling in these two computations, using predictive coding computation as a common reference, and shows that each of these computations recruits distinct laminar circuits, particularly in layer 5, depending on the cognitive demands. These findings highlight many open questions, including how different interareal feedback pathways, originating from and terminating at different layers, convey distinct functional signals.
It has long been argued that only humans could produce and understand language. But now, for the first time, artificial language models (LMs) achieve this feat. Here we survey the new purchase LMs are providing on the question of how language is implemented in the brain. We discuss why, a priori, LMs might be expected to share similarities with the human language system. We then summarize evidence that LMs represent linguistic information similarly enough to humans to enable relatively accurate brain encoding and decoding during language processing. Finally, we examine which LM properties—their architecture, task performance, or training—are critical for capturing human neural responses to language and review studies using LMs as in silico model organisms for testing hypotheses about language. These ongoing investigations bring us closer to understanding the representations and processes that underlie our ability to comprehend sentences and express thoughts in language.
Predictive processing is a computational framework that aims to explain how the brain processes sensory information by making predictions about the environment and minimizing prediction errors. It can also be used to explain some of the key symptoms of psychotic disorders such as schizophrenia. In recent years, substantial advances have been made in our understanding of the neuronal circuitry that underlies predictive processing in cortex. In this review, we summarize these findings and how they might relate to psychosis and to observed cell type–specific effects of antipsychotic drugs. We argue that quantifying the effects of antipsychotic drugs on specific neuronal circuit elements is a promising approach to understanding not only the mechanism of action of antipsychotic drugs but also psychosis. Finally, we outline some of the key experiments that should be done. The aims of this review are to provide an overview of the current circuit-based approaches to psychosis and to encourage further research in this direction.
Auditory processing in mammals begins in the peripheral inner ear and extends to the auditory cortex. Sound is transduced from mechanical stimuli into electrochemical signals of hair cells, which relay auditory information via the primary auditory neurons to cochlear nuclei. Information is subsequently processed in the superior olivary complex, lateral lemniscus, and inferior colliculus and projects to the auditory cortex via the medial geniculate body in the thalamus. Recent advances have provided valuable insights into the development and functioning of auditory structures, complementing our understanding of the physiological mechanisms underlying auditory processing. This comprehensive review explores the genetic mechanisms required for auditory system development from the peripheral cochlea to the auditory cortex. We highlight transcription factors and other genes with key recurring and interacting roles in guiding auditory system development and organization. Understanding these gene regulatory networks holds promise for developing novel therapeutic strategies for hearing disorders, benefiting millions globally.
The cerebellum has a well-established role in controlling motor functions, including coordination, posture, and the learning of skilled movements. The mechanisms for how it carries out motor behavior remain under intense investigation. Interestingly though, in recent years the mechanisms of cerebellar function have faced additional scrutiny since nonmotor behaviors may also be controlled by the cerebellum. With such complexity arising, there is now a pressing need to better understand how cerebellar structure, function, and behavior intersect to influence behaviors that are dynamically called upon as an animal experiences its environment. Here, we discuss recent experimental work that frames possible neural mechanisms for how the cerebellum shapes disparate behaviors and why its dysfunction is catastrophic in hereditary and acquired conditions—both motor and nonmotor. For these reasons, the cerebellum might be the ideal therapeutic target.
Since its recent discovery, the meningeal lymphatic system has reshaped our understanding of central nervous system (CNS) fluid exchange, waste clearance, immune cell trafficking, and immune privilege. Meningeal lymphatics have also been demonstrated to functionally modify the outcome of neurological disorders and their responses to treatment, including brain tumors, inflammatory diseases such as multiple sclerosis, CNS injuries, and neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. In this review, we discuss recent evidence of the contribution of meningeal lymphatics to neurological diseases, as well as the available experimental methods for manipulating meningeal lymphatics in these conditions. Finally, we also provide a discussion of the pressing questions and challenges in utilizing meningeal lymphatics as a prime target for CNS therapeutic intervention and possibly drug delivery for brain disorders.
The hippocampus is critical for memory and spatial navigation. The ability to map novel environments, as well as more abstract conceptual relationships, is fundamental to the cognitive flexibility that humans and other animals require to survive in a dynamic world. In this review, we survey recent advances in our understanding of how this flexibility is implemented anatomically and functionally by hippocampal circuitry, during both active exploration (online) and rest (offline). We discuss the advantages and limitations of spike timing–dependent plasticity and the more recently discovered behavioral timescale synaptic plasticity in supporting distinct learning modes in the hippocampus. Finally, we suggest complementary roles for these plasticity types in explaining many-shot and single-shot learning in the hippocampus and discuss how these rules could work together to support the learning of cognitive maps.
To perform computations with the efficiency necessary for animal survival, neocortical microcircuits must be capable of reconfiguring in response to experience, while carefully regulating excitatory and inhibitory connectivity to maintain stable function. This dynamic fine-tuning is accomplished through a rich array of cellular homeostatic plasticity mechanisms that stabilize important cellular and network features such as firing rates, information flow, and sensory tuning properties. Further, these functional network properties can be stabilized by different forms of homeostatic plasticity, including mechanisms that target excitatory or inhibitory synapses, or that regulate intrinsic neuronal excitability. Here we discuss which aspects of neocortical circuit function are under homeostatic control, how this homeostasis is realized on the cellular and molecular levels, and the pathological consequences when circuit homeostasis is impaired. A remaining challenge is to elucidate how these diverse homeostatic mechanisms cooperate within complex circuits to enable them to be both flexible and stable.
Seeing in three dimensions is a major property of the visual system in mammals. The circuit underlying this property begins in the retina, from which retinal ganglion cells (RGCs) extend to the same or opposite side of the brain. RGC axons decussate to form the optic chiasm, then grow to targets in the thalamus and midbrain, where they synapse with neurons that project to the visual cortex. Here we review the cellular and molecular mechanisms of RGC axonal growth cone guidance across or away from the midline via receptors to cues in the midline environment. We present new views on the specification of ipsi- and contralateral RGC subpopulations and factors implementing their organization in the optic tract and termination in subregions of their targets. Lastly, we describe the functional and behavioral aspects of binocular vision, focusing on the mouse, and discuss recent discoveries in the evolution of the binocular circuit.
The intricate network of the brain's neurons and synapses poses unparalleled challenges for research, distinct from other biological studies. This is particularly true when dissecting how neurons and their functional units work at a cell biological level. While traditional microscopy has been foundational, it was unable to reveal the deeper complexities of neural interactions. However, an imaging renaissance has transformed our capabilities. Advancements in light and electron microscopy, combined with correlative imaging, now achieve unprecedented resolutions, uncovering the most nuanced neural structures. Maximizing these tools requires more than just technical proficiency. It is crucial to align research aims, allocate resources wisely, and analyze data effectively. At the heart of this evolution is interdisciplinary collaboration, where various experts come together to translate detailed imagery into significant biological insights. This review navigates the latest developments in microscopy, underscoring both the promise of and prerequisites for bending this powerful tool set to understanding neuronal cell biology.
In the natural world, animals make decisions on an ongoing basis, continuously selecting which action to undertake next. In the lab, however, the neural bases of decision processes have mostly been studied using artificial trial structures. New experimental tools based on the genetic toolkit of model organisms now make it experimentally feasible to monitor and manipulate neural activity in small subsets of neurons during naturalistic behaviors. We thus propose a new approach to investigating decision processes, termed reverse neuroethology. In this approach, experimenters select animal models based on experimental accessibility and then utilize cutting-edge tools such as connectomes and genetically encoded reagents to analyze the flow of information through an animal's nervous system during naturalistic choice behaviors. We describe how the reverse neuroethology strategy has been applied to understand the neural underpinnings of innate, rapid decision making, with a focus on defensive behavioral choices in the vinegar fly Drosophila melanogaster.
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This scientific commentary refers to ‘Visual feature processing in a large stroke cohort: evidence against modular organization’ by Lugtmeijer, Sobolewska et al. (https://doi.org/10.1093/brain/awaf009).
AbstractParkinson’s disease is characterized, in part, by hypoactivity of direct pathway inhibitory projections from striatum to the globus pallidus internus (GPi) and indirect pathway inhibitory projections from globus pallidus externus (GPe) to the subthalamic nucleus (STN). In people with Parkinson’s disease (n=32), we explored the potential use of intracranial stimulation for eliciting long-term potentiation (LTP) of these underactive pathways to produce improvement of symptoms that persists beyond stimulation cessation.During GPi deep brain stimulation (DBS) surgery, we found strong evidence (p<.05; BF10>10) of increased amplitudes of hand movements and striato-GPi evoked potentials before versus after high-frequency microstimulation. In a small sample of outpatients with sensing-enabled GPi-DBS, we found anecdotal evidence (p<.10; BF10>1) of improved hand movements and attenuated beta frequency oscillations. In STN, enduring behavioural effects, potentiation of GPe-STN projections (intraoperative), and decreases to beta oscillations (extraoperative) were not observed.Our findings support that LTP-like effects in GPi may produce motor improvements that extend beyond stimulation cessation, while the lack of effects in STN suggests the need for optimizing stimulation paradigms for effective LTP induction. These findings nevertheless highlight the potential of LTP-based strategies for sustained therapeutic benefits, which may be useful for mitigating DBS side-effects and optimizing battery usage.
AbstractPatients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, often present with severe psychiatric symptoms, yet the neuropathological mechanisms underlying their cognitive deficits remain insufficiently understood. In this study, we constructed an animal model using anti-NMDAR IgG purified from the serum of patients with anti-NMDAR encephalitis, and we used IgG obtained from healthy individuals as a control. Daily administration of anti-NMDAR IgG into the medial prefrontal cortex (mPFC) of mice for 7 days resulted in cognitive impairments resembling clinical symptoms, which spontaneously resolved 30 days after discontinuing the injections.Immunohistochemical staining and electrophysiological testing of parvalbumin neurons in the mPFC treated with anti-NMDAR IgG revealed significant cellular morphological damage, reduced excitability, synaptic dysfunction and a loss of NMDAR antagonist-induced gamma oscillations. Application of optogenetic and pharmacogenetic techniques to activate parvalbumin neurons in the mPFC successfully reversed the cognitive impairments observed in the anti-NMDAR-IgG-treated mice. Single-cell sequencing of anti-NMDAR-IgG-treated parvalbumin neurons identified differentially expressed genes and pathways related to synapses and neuronal development, offering potential targets for therapeutic intervention. Additionally, we showed that these alterations in parvalbumin neurons were not confined to the mPFC, as similar changes were detected in the hippocampus after anti-NMDAR IgG injections.In summary, our findings elucidate distinct alterations in parvalbumin neurons during the pathogenesis of anti-NMDAR encephalitis, providing preclinical rationale for exploring approaches to modulate parvalbumin neuronal function to treat anti-NMDAR encephalitis.
AbstractIschemic strokes disrupt brain networks, leading to remote effects in key regions like the thalamus, a critical hub for brain functions. However, non-invasive methods to quantify these remote consequences still need to be explored. This study aimed to demonstrate that MRI-derived R2* changes can capture iron accumulation linked with inflammation secondary to stroke-induced disconnection.In order to link remote R2* changes to stroke-induced disconnection, we first conducted a secondary analysis of 156 prospectively included stroke patients who underwent MRI at baseline and 1-year follow-up. We mapped fibers disconnected by baseline infarcts to compare the R2* changes over 1 year according to the disconnectivity status in specific thalamic nuclei groups. We also identified the variables associated with elevated R2* at 1 year in a multivariate context through linear regressions. In parallel, to understand the biological underpinning of the remote R2* changes, we set up a translational mouse model through photothrombotic induction of focal cortical infarcts or sham procedures in 110 C57BL/6J mice. We explored the mice through combinations of in vivo MRI at 72h, 2-, 4-, and 8-weeks, histology, qPCR for gene expression, mass spectrometry for iron concentration quantification, and additional ex vivo high-resolution diffusion tensor imaging.In stroke patients, we found a significant increase of R2* within severely disconnected medial and lateral thalamic nuclei groups from baseline to 1 year. At the same time, no change occurred if these structures were not disconnected. We also showed that the disconnectivity status at baseline was significantly associated with R2* at follow-up, independently from confounders, establishing a direct and independent relationship between baseline disconnection and the subsequent R2* increase within the associated locations. In mice, we recapitulated the patients’ conditions by observing increased R2* in the stroke groups, specifically within the disconnected thalamic nuclei. Such remote and focal R2* changes peaked at 2 weeks, preceding and correlating with longer-term atrophy at 8 weeks. We established that the remote R2* increase was spatially and temporally correlated with a significant increase of chemically determined iron load bound to ferritin within activated microglial cells.This study provides critical evidence that R2* is a sensitive marker of inflammation secondary to network disconnection, potentially informing future neuroprotective strategies targeting remote brain regions after stroke.
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AbstractAfter stroke, upper extremity (UE) motor recovery may be mediated in part by transcallosal projections between hemispheres. The interhemispheric competition model posits that transcallosal inhibition (TI) from the contralesional hemisphere is abnormally strengthened following stroke and interferes with motor recovery. This model has recently been questioned.In this longitudinal study, we aimed to definitively confirm or refute a maladaptive role of contralesional TI in subacute motor recovery.We assessed 30 mild-to-moderately impaired subjects over the six months following ischemic stroke. We tracked contralesional TI and motor functions in the proximal and distal segments of the paretic UE. We used transcranial magnetic stimulation to examine the ipsilateral silent period (iSP) in an arm and hand muscle. We used quantitative and clinical testing to examine deficits in muscle strength, motor control, and individuation; UE segmental impairment; and UE activity limitation. We assessed the relationships of contralesional TI to motor functions in the subacute period.Despite recovery of most motor functions in the proximal and distal UE, contralesional TI was largely static and unrelated to recovery of any motor function. There were inconsistent associations between stronger TI, less hand impairment, and less activity limitation in the subacute period overall.We found no compelling evidence to suggest a maladaptive role of contralesional TI in UE motor recovery in mild-to-moderately impaired stroke subjects. The scattered associations between stronger TI and better levels of paretic UE function suggest a potential supportive role rather than a limiting one. These findings challenge the validity of the interhemispheric competition model in the subacute recovery period, and prompt reconsideration of neuromodulatory strategies that subacutely target contralesional TI.
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AbstractRaised intracranial pressure (ICP) is associated with altered cerebral hemodynamics and cephalic pain. The relationship between the algetic response and cortical neurovascular changes in raised ICP is unclear. This study aimed to evaluate this relationship and determine if lowering ICP (using a glucagon like peptide-1 receptor agonist) could ameliorate the algetic response. We also sought to explore the role of calcitonin gene-related peptide in cephalic pain driven by raised ICP by inhibiting calcitonin gene-related peptide signalling and quantifying changes in the algetic response.In a rat model of raised ICP, created by intracisternal kaolin injection, mechanical thresholds were measured alongside steady-state potential and cerebral blood flow responses to spreading depolarisation. Nuclear magnetic resonance spectroscopy evaluated energetic substrates in animals with raised ICP ex-vivo. Glucagon like peptide-1 receptor agonist exenatide and calcitonin gene-related peptide receptor antagonist olcegepant were injected daily and measurements were repeated.Kaolin increased ICP [median (range) 15.96mmHg (8.97) n = 8] versus controls [6.02mmHg (1.79) n = 6 p = 0.0007]. Animals with raised ICP exhibited reduced mechanical thresholds (mean (SD) hind paw baseline: 5.78g (2.81), day 7: 3.34g (2.22) p < 0.001, periorbital baseline: 6.13g (2.07), day 7: 2.35g (1.91) n = 12 p < 0.001). Depolarisation and repolarisation durations were increased [depolarisation raised ICP: 108.81s (222.12) n = 11, controls: 37.54s (108.38) n = 9 p = 0.038, repolarisation raised ICP: 1824.26s (3499.54) n = 12, controls: 86.96s (140.05) n = 9 p<0.0001]. CBF change was also reduced (85.55% (30.84) n = 9) compared to controls (217.64% (37.70) n = 8 p < 0.0001). Substrates for cellular energetics (ADP, ATP and NAD+) were depleted in rodent brains with raised ICP (p = 0.009, p = 0.018, p = 0.011 respectively).Exenatide significantly lowered ICP (exenatide: 9.74mmHg (6.09) n = 19, vehicle: 18.27mmHg (6.67) n = 16 p = 0.004) and rescued changes in mechanical withdrawal. Exenatide recovered characteristic spreading depolarisation responses (depolarisation duration exenatide: 56.46s (25.10) n = 7, vehicle: 115.98s (58.80) n = 6 p = 0.033) [repolarisation duration exenatide: 177.55s (562.88) n = 7, vehicle: 800.85s (1988.67) n = 6 p = 0.002]. In the setting of raised ICP olcegepant prevented changes in periorbital mechanical thresholds.We conclude that raised ICP disrupted the cortical neurovascular responses, reduced algetic thresholds and depleted crucial energetic substrates. Exenatide reduced ICP, improving algetic thresholds and cortical neurovascular changes. Importantly, olcegepant alleviated the cerebral algesia, suggesting calcitonin gene-related peptide’s role in driving pain responses in elevated ICP.These studies support the rationale that reducing ICP improves cephalic pain in conditions of raised ICP. Furthermore, the data suggests that headache pain, in diseases associated with raised ICP, could be therapeutically ameliorated though blockade of the calcitonin gene-related peptide pathway.
AbstractMalformations of cortical development (MCDs) are a heterogeneous family of congenital brain malformations that originate from disturbed development of the cerebral cortex. MCDs can arise from primary genetic disorders that lead to dysfunction of the molecular processes controlling neuronal proliferation, neuronal migration, cortical folding, or cortical organization. MCDs can also result from secondary, disruptive causes, such as congenital infection or other in utero brain injuries. Sequelae of MCDs can include epilepsy, intellectual disability, and cerebral palsy, among other symptoms, with a high burden of pediatric morbidity. Advances in antenatal genetic testing and imaging have improved the ability to diagnose MCDs, yet limited literature exists to aid clinicians in prognostication of outcomes and perinatal management. These clinical realities can make it challenging for clinicians caring for fetal neurological conditions to counsel families and make recommendations for interdisciplinary care. We aim to review the literature on fetal MCDs and present practice guidelines for clinicians regarding the pre- and postnatal management of MCDs.
AbstractNeuromyelitis optica (NMO) is an acute inflammatory demyelinating disease of the CNS. The presence of astrocyte-targeted AQP4-immunoglobulin G (IgG) in peripheral blood is a major factor in its diagnosis. Previous studies show that AQP4-IgG directly contributes to CNS inflammation, and B cells play a central pathogenic role in NMO. However, where and how B cell response is altered remains controversial. In this study, we comprehensively analyzed with high-parameter flow cytometry the immune cell populations in the CSF samples obtained from first-episode acute-phase NMO patients, and compared to those from patients with acute-phase Multiple Sclerosis (MS) and other neurological diseases (OND). Among ten immune cell populations defined in the analysis, only the frequency of B cells and antibody-secreting cells (ASC) were higher in the CSF of acute-phase NMO compared to OND. Detailed assessments of B cell and ASC subsets in the CSF revealed differences in the dominant subsets between NMO and MS. In NMO, a series of CD21lo B cell subsets ranging from “activated” naïve B, double negative, and switched memory, thus subsets considered as ASC-precursors, were dominant. A majority of these CD21lo B cell subsets expressed CD69 and CXCR3, suggesting their CNS residency. An increase of CD21lo B cell subsets was also observed in the CSF of treatment-refractory NMO patients. Furthermore, two B helper T cell subsets, T peripheral helper type1 and T follicular helper type1 cells, both highly expressing CD69 and CXCR3, were enriched in the CSF of NMO patients, suggesting their interactions with ASC-precursors in the CNS. In vitro culture experiments using blood samples from patients with NMO showed that CD21lo B cells contained AQP4-IgG-producing cells and displayed a high propensity to differentiate into ASCs. We further found that CD21lo B cell subsets in NMO upregulated the expression of C5a receptors, and C5a signals promoted their differentiation into ASCs. ASCs derived from CD21lo B cells expressed high levels of CXCR3 and CD138. The increase in CD21lo B cell subsets significantly correlated with the annual relapse rate. Collectively, our study highly suggests that the mechanism to promote the generation of CD21lo B cells, likely via the extrafollicular pathway, becomes activated during the acute phase of NMO, and the generated CD21lo B cell subsets contribute to the pathogenesis. Targeting CD21lo B cell subsets might be useful for the development of novel therapeutic approaches.
AbstractEpilepsy is recognised as one of the leading targets for precision medicine, following on from the successes in cancer therapy, due to its substantial clinical heterogeneity and divergent therapeutic options. To bring personalised care to the epilepsies, there is a need for appropriate precision biomarkers that can identify disease processes or predict treatment outcomes at the individual patient level. Neuroimaging techniques, including magnetic resonance imaging (MRI), have been transformative for clinical practice, particularly in medically refractory focal epilepsies. Advanced MRI techniques have the potential to bring precision medicine clearly into view for epileptology; however, there are challenges that must be overcome before cutting-edge neuroimaging tools can be used in clinical practice. In this Review article, we communicate our view that implementation of normative modelling frameworks will help to deliver robust quantitative MRI biomarkers for individualized prediction. Here, we provide recommendations for researchers and clinicians alike, from careful research design to clinical applications, that will help to identify diagnostic and predictive imaging biomarkers. Such precision markers will be key to delivering personalised medicine for the epilepsies.
AbstractImpulse control disorders (ICDs) are frequent and particularly distressing neuropsychiatric symptoms in patients with Parkinson’s disease (PD) which are related to impaired behavioural inhibition. Multiple PET imaging studies indicate that striatal dopaminergic abnormalities contribute to hyperdopaminergic functioning in PD patients with ICD (PDICD+) and to the dysregulation of the limbic fronto-striatal networks which are critical for reward-related decision impulsivity. However, the serotonergic system is central to response inhibition and plays a critical role in neuropsychiatric symptoms in PD, but its role remains undetermined in PDICD. We hypothesized that PDICD+ patients exhibit serotonergic dysfunction within the cortico-striato-pallido-thalamic circuits involved in the inhibitory control of behaviour and decided to investigate the pre- and post-synaptic serotonergic innervation using two highly-specific PET tracers for the serotonin transporter (SERT) using [11C]DASB and the 5-HT2A receptor using [18F]altanserin.In this prospective, case-control, double-tracer PET study, we recruited 15 PDICD+ patients, 15 PDICD- patients and 15 healthy controls, matched for age and sex, and compared the availability of [11C]DASB and [18F]altanserin using permutation-based analysis.PDICD+ patients had one (n=9) or multiple ICDs (n=6), consisting in hypersexuality (n=8), compulsive eating (n=6), compulsive shopping (n=5) and pathological gambling (n=4) and were characterized by greater choice impulsivity (impaired delay discounting for monetary rewards) and greater urgency with more severe depressive and anxious symptoms. We demonstrate that PDICD+ patients had greater [11C]DASB binding in the posterior putamen and pallidum in comparison to PDICD- patients, corresponding to relatively preserved presynaptic SERT availability within the subcortical sensorimotor network involved in response inhibition. In addition, cortical [18F]altanserin binding was greater in PDICD+ patients in the bilateral supplementary motor area, precentral gyrus and right dorsolateral prefrontal cortex, involving the sensorimotor and associative networks which regulate behavioural inhibition. Furthermore, we show that pre- and post-synaptic serotonergic dysfunction subserving action versus decision impulsivity in PD patients specifically followed the distinctive functional organization of the sensorimotor and associative fronto-striatal networks.Altogether, we demonstrate that serotonergic dysfunction related to ICDs in PD specifically involve the sensorimotor and associative cortico-striato-pallido-thalamic circuits involved in inhibitory control. Thus, serotonergic dysfunction contributes to the mechanisms related to the vulnerability and development of ICDs in PD patients, beyond the known dopaminergic abnormalities in the limbic fronto-striatal circuit.
AbstractWhiplash Associated Disorders (WAD) affect 20-50 million individuals globally each year, with up to 50% developing persistent pain. WAD grade II (WADII) is the most common type and is characterised by neck symptoms and musculoskeletal signs without apparent nerve injury on routine diagnostic testing. However, emerging evidence suggests nerve pathology may be present in some people with WADII. This longitudinal cohort study aimed to comprehensively investigate the presence, temporal patterns, and prognostic value of nerve pathology and neuropathic pain in acute WADII.A prospective longitudinal cohort study was conducted with 129 acute participants with WADII (median age 36.0 years, 58% female) and 36 healthy controls (median age 39.0 years, 61% female). Participants with WADII were recruited within four weeks of injury from local emergency departments. Data collection included bedside neurological assessments, quantitative sensory testing (QST), intraepidermal nerve fibre density, and serum neurofilament light chain (NfL) concentrations. Follow-up assessments were conducted 6-months after injury.Signs of neuropathic pain were present in 65% (84/129) acutely and persisted in 32% (21/66) 6-months post-injury. Bedside neurological assessment revealed somatosensory loss of function was present in 54% (70/129) acutely reducing to 25% (17/67) 6-months post-injury. QST demonstrated significantly reduced cold, warm, thermal sensory limen, mechanical, and vibration detection thresholds in acute WADII compared to controls (d>0.47). Acute loss of function in at least one QST parameter was present in 67.6% (85/126) of WADII. At 6-months, participants with WADII showed persistent hypoaesthesia to warm, thermal sensory limen, and mechanical detection thresholds, and decreased mechanical pain and pressure pain sensitivity compared to controls (d>0.44).These functional neurological changes were accompanied by elevated serum neurofilament light chain levels in acute WADII compared to controls (d=-0.52 (95% confidence interval -0.94, -0.10). Intraepidermal nerve fibre densities at the index finger were not significantly different between groups. However, dermal MBP+/PGP+ myelinated nerve bundles at the index finger were reduced 6-months post-injury in WADII compared to controls (d=0.69 (0.26, 1.11). Multivariable linear regression suggested bedside tests for hypoaesthesia at the index finger were prognostic for whiplash-related upper quadrant pain 6-months post-injury (r2=0.13, p=0.02).In conclusion, two-thirds of participants with acute WADII initially exhibited signs of neuropathic pain and nerve pathology. At the 6-month follow-up, neuropathic pain persisted in one-third of participants with WADII, while nerve pathology persisted in two-thirds. These findings challenge the traditional musculoskeletal classification of WADII and underscore the need for targeted neurological assessments and treatment.
Yang et al. propose that psychedelics hold untapped potential for improving stroke recovery through their unique ability to modulate neuroplasticity, reduce neuroinflammation, and enhance cognitive and psychological resilience.
AbstractChildren who experienced moderate perinatal hypoxia are at risk of developing long-lasting subtle cognitive and behavioural deficits, including learning disabilities and emotional problems. Understanding the underlying mechanisms is an essential step for designing targeted therapy. Fast-spiking, parvalbumin-positive (PV) GABAergic interneurons modulate the generation of gamma oscillations, which in turn regulate many cognitive functions including goal-directed attentional processing and cognitive flexibility. Due to their fast-firing rate, PV cell function requires high levels of energy, which may render them highly vulnerable to conditions of metabolic and oxidative stress caused by perinatal hypoxia.Here, we show that adult mice that experienced moderate perinatal hypoxia (MPH) have decreased cortical PV expression levels in addition to specific impairments in social behaviour, recognition memory and cognitive flexibility. We further found that the expression level of the neurotrophin receptor p75NTR, which limits PV cell maturation during the first postnatal weeks, is increased in MPH mice. Genetic deletion of p75NTR in GABAergic neurons expressing the transcription factor Nkx2.1, which include PV cells, protects mice from PV expression loss and the long-term cognitive effects of MPH. Finally, treatment with a p75NTR inhibitor starting after MPH and lasting for a week, prevented PV expression loss and the occurrence of cognitive and cortical activity deficits in adult mice.Altogether our data reveals p75NTR-mediated signaling, as a potential molecular target, for the treatment of the cognitive alterations caused by MPH.
AbstractProteins are involved in multiple biological functions. High-throughput technologies have allowed the measurement of thousands of proteins in population biobanks. In this study, we aimed to identify proteins related to Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and amyotrophic lateral sclerosis by leveraging large-scale genetic and proteomic data.We performed a two-sample cis Mendelian randomization study by selecting instrumental variables for the abundance of >2700 proteins measured by either Olink or SomaScan platforms in plasma from the UK Biobank and the deCODE Health Study. We also used the latest publicly available genome-wide association studies for the neurodegenerative diseases of interest. The potentially causal effect of proteins on neurodegenerative diseases was estimated based on the Wald ratio.We tested 13 377 protein–disease associations, identifying 169 associations that were statistically significant (5% false discovery rate). Evidence of co-localization between plasma protein abundance and disease risk (posterior probability > 0.80) was identified for 61 protein–disease pairs, leading to 50 unique protein–disease associations. Notably, 23 of 50 protein–disease associations corresponded to genetic loci not previously reported by genome-wide association studies. The two-sample Mendelian randomization and co-localization analysis also showed that APOE abundance in plasma was associated with three subcortical volumes (hippocampus, amygdala and nucleus accumbens) and white matter hyper-intensities, whereas PILRA and PILRB abundance in plasma was associated with caudate nucleus volume.Our study provided a comprehensive assessment of the effect of the human proteome that is currently measurable through two different platforms on neurodegenerative diseases. The newly associated proteins indicated the involvement of complement (C1S and C1R), microglia (SIRPA, SIGLEC9 and PRSS8) and lysosomes (CLN5) in Alzheimer’s disease; the interleukin-6 pathway (CTF1) in Parkinson’s disease; lysosomes (TPP1), blood–brain barrier integrity (MFAP2) and astrocytes (TNFSF13) in amyotrophic lateral sclerosis; and blood–brain barrier integrity (VEGFB), oligodendrocytes (PARP1), node of Ranvier and dorsal root ganglion (NCS1, FLRT3 and CDH15) and the innate immune system (CR1, AHSG and WARS) in multiple sclerosis. Our study demonstrates how harnessing large-scale genomic and proteomic data can yield new insights into the role of the plasma proteome in the pathogenesis of neurodegenerative diseases.
AbstractTuberous sclerosis complex (TSC) is an inherited multi-system neurocutaneous disorder where patients often present with neurodevelopmental manifestations such as epilepsy and TSC-associated neuropsychiatric disorder (TAND) that includes autism spectrum disorder (ASD). TSC is caused by inactivating mutations in TSC1 or TSC2 tumor suppressor genes, with encoded proteins hamartin (TSC1) and tuberin (TSC2) forming a functional complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) signaling. This has led to treatment with allosteric mTORC1 inhibitor rapamycin analogs (“rapalogs”) for TSC tumors; however, rapalogs are ineffective for treating neurodevelopmental manifestations. mTORC1 signaling controls protein synthesis by regulating formation of the eIF4F complex, with further modulation by MNK1/2 kinases via phosphorylation of the eIF4F subunit eIF4E. While both these pathways modulate translation, comparing their impact on transcriptome-wide mRNA translation, as well as effects of inhibiting these pathways in TSC has not been explored.Employing CRISPR-modified, isogenic neural progenitor cells (NPCs) derived from a female TSC2 patient, we have examined alterations in early neurodevelopmental phenotypes including proliferation and neurite outgrowth, as well as ability of bi-steric mTORC1-specific inhibitor RMC-6272 to rescue these phenotypes. Further, we utilized polysome-profiling to examine transcriptome-wide changes in mRNA translation upon TSC2 loss and tested effects of treatment with RMC-6272 or MNK1/2-specific inhibitor eFT-508.Our results reveal that altered early neurodevelopmental phenotypes can be rescued upon treatment with RMC-6272, but not rapamycin. We also discovered dysregulated mRNA translation in TSC2-Null NPCs, which significantly overlaps with the translatome from TSC1-Null NPCs. Interestingly, numerous non-monogenic ASD-, NDD- and epilepsy-associated genes identified in patients harboring putative loss-of-function mutations, were translationally suppressed in TSC2-Null NPCs. Importantly, translation of these ASD- and NDD-associated genes was reversed upon inhibition of either mTORC1 or MNK1/2 signaling using RMC-6272 or eFT-508, respectively.This study establishes the importance of mTORC1-eIF4F- and MNK-eIF4E-sensitive mRNA translation in TAND, ASD and other neurodevelopmental disorders laying the groundwork for evaluating drugs in clinical development that target these pathways as a treatment strategy for these disorders.
This scientific commentary refers to ‘Distinctive clinical features in biopsy-proven nerve large-arteriole vasculitis and microvasculitis’ by Soontrapa et al. (https://doi.org/10.1093/brain/awae406).
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AbstractGeneral paresis is a rare type of syphilis characterized by progressive cognitive impairment and psychiatric syndromes. It is often misdiagnosed because of its rarity and similarity with other diseases. We aimed to comprehensively investigate the clinical, radiological, pathological, and prognostic features of general paresis, and compare it with other dementias.Between August 2019 and January 2024, patients were recruited from a Memory Clinic Setting of National Center for Neurological Disorders in China. Participants underwent clinical evaluation, laboratory testing, and imaging, and were followed after treatment. Comparative analysis was conducted on clinical features and neuropsychiatric assessments, while brain image features were investigated using linear regression models and SuStaIn models.Seventy-eight patients were included, with 90% being male. The median duration from symptom onset to the first diagnostic visit was 15 months. Sixty-three patients were followed for an average of 1.4 years. Cognitive impairment emerged as the most common symptom, with half of the patients co-existed with motor symptoms. Impairment across all cognitive domains accompanied by positive psychiatric symptoms raised suspicion for general paresis, and distinguishing it from Alzheimer’s disease, frontotemporal dementia, and anti-LGI1 encephalitis-related dementia. Common imaging abnormalities in general paresis included whole brain atrophy and cortical hypointensity. The hippocampal-predominant and hippocampal-sparing atrophy subtypes were identified. Autoimmune responses in general paresis were demonstrated through the detection of autoimmune encephalitis antibodies in 11% of patients. Pathological amyloid changes were observed in 26% of patients, while elevated total tau levels were found in 30%. Seventy percent of patients showed improvement following treatment, with a reduction in the number of symptoms observed across all cases.This study identifies specific clinical syndromes and radiological features of general paresis and refines the understanding of its prognosis. We provide clues to distinguish general paresis from other dementias, facilitating early diagnosis and treatment. The role of novel pathological changes in general paresis needs to be further studied.
AbstractProtease activated receptor 2 (PAR2) is a G-protein coupled receptor expressed in meningeal neurons, fibroblasts and mast cells that may be targeted to treat migraine. MEDI0618, a fully humanized PAR2 monoclonal antibody, engineered to enhance FcRn-dependent recycling and currently in clinical development, was evaluated in human and rodent in vitro assays, in multiple murine in vivo migraine models and in a model of post-traumatic headache.MEDI0618 bound specifically and with high affinity to cells expressing human PAR2 (hPAR2) and prevented matriptase-induced increase in cytosolic calcium. Similarly, MEDI0618 prevented matriptase-induced calcium in primary fibroblasts and microvascular endothelial cells from human dura mater. MEDI0618 had no effect on hPAR1 receptors. Single-cell calcium imaging of acutely dissociated mouse trigeminal ganglion neurons confirmed expression and functionality of mouse PAR2. Studies in vivo used evoked cutaneous allodynia as a surrogate of headache-like pain and, in some experiments, rearing as a measure of non-evoked headache pain. MEDI0618 was administered subcutaneously to C57BL6/J female mice prior to induction of migraine-like pain with (i) systemic nitroglycerin or compound 48/80 (mast cell degranulator); or (ii) with supradural compound 48/80 or an inflammatory mediator (IM) cocktail. To assess possible efficacy against CGRP receptor (CGRP-R)-independent pain, MEDI0618 was also evaluated in the IM model in animals pretreated with systemic olcegepant (CGRP-R antagonist). Migraine-like pain was also induced by inhalational umbellulone, a TRPA1 agonist, in animals primed with restraint stress in the presence or absence of MEDI0618 as well as in a model of post-traumatic headache pain induced by a mild traumatic brain injury.MEDI0618 prevented cutaneous allodynia elicited by systemic nitroglycerin, compound 48/80 and from supradural compound 48/80 and IM. Systemic olcegepant completely blocked periorbital cutaneous allodynia induced by supradural CGRP but failed to reduce IM-induced cutaneous allodynia. In contrast, MEDI0618 fully prevented IM-induced cutaneous allodynia, regardless of pretreatment with olcegepant. Umbellulone elicited cutaneous allodynia only in restraint stress-primed animals, which was prevented by MEDI0618. MEDI0618 prevented the decrease in rearing behaviour elicited by compound 48/80. However, MEDI0618 did not prevent mild traumatic brain injury-related post-traumatic headache measures.These data indicate that MEDI0618 is a potent and selective inhibitor of PAR2 that is effective in human and rodent in vitro cell systems. Further, blockade of PAR2 with MEDI0618 was effective in all preclinical migraine models studied but not in a model of post-traumatic headache. MEDI0618 may represent a novel therapy for migraine prevention with activity against CGRP-dependent and independent attacks.
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AbstractNeuroinflammation is a feature of many neurodegenerative diseases, and is quantified in vivo by PET imaging with radioligands for the translocator protein (TSPO, e.g. [11C]-PK11195). TSPO radioligand binding correlates with clinical severity and predicts clinical progression. However, the cellular substrate of altered TSPO binding is controversial and requires neuropathological validation.We used progressive supranuclear palsy (PSP) as a demonstrator condition, to test the hypothesis that [11C]-PK11195 PET reflects microglial changes. We included people with PSP-Richardson’s syndrome who had undergone [11C]-PK11195 PET in life (n=8). In post-mortem brain tissue from the same participants, we characterised cell-type specific TSPO expression and quantified microgliosis in eight cortical and eleven subcortical regions.Double-immunofluorescence labelling for TSPO and cell markers showed TSPO expression in microglia, astrocytes, and endothelial cells. Microglial (and not astrocytic) TSPO levels were higher in donors with PSP compared to controls (n=3), and correlated with changes in microglial density. There was a significant positive correlation between regional [11C]-PK11195 binding potential ante-mortem and the density of post-mortem CD68+ phagocytic microglia, as well as microglial TSPO levels.We conclude that in vivo disease-related changes in [11C]-PK11195 binding is largely driven by microglia and can be interpreted as a biomarker of microglia-mediated neuroinflammation in tauopathies.
AbstractWhile neuropathological and genetic studies have established the crucial involvement of TDP-43 proteinopathy in the pathogenesis of ALS (Amyotrophic Lateral Sclerosis), FTD (Frontotemporal Dementia) and related neurodegenerative disorders, multiple studies have described the presence of TDP-43 inclusions in muscular disorders, including inclusion body myositis but also other related rimmed vacuole myopathies. In addition, TDP-43 has been reported to be essential in normal muscle physiology as it is implicated in the formation of so-called amyloid-like myogranules during normal muscle regeneration after injury. However, genetic evidence supporting a primary role for TDP-43 proteinopathy in muscle disease has been missing. In the present review we highlight recent landmark discoveries linking novel pathogenic TDP-43 variants [p.(W385IfsX10) and p.(G376V)] within the prion-like domain with unusual aggregation-propensity and muscle rather than neuronal pathology. We discuss these studies in the context of known TDP-43-related pathways in ALS/FTD pathogenesis and show how they challenge some widely accepted views such as ALS as a pure neurogenic presynaptic neuromuscular disease and the direct correlation between TDP-43 aggregation-propensity and neurotoxicity. Finally, we discuss TDP-43 as part of a growing list of RNA-binding proteins including hnRNPA2B1 and hnRNPA1 as genetic causes of myopathies and relate this to the idea of ‘multisystem proteinopathy’.
AbstractFunctional neuroimaging has provided several new tools for improving both the diagnosis and prognosis in patients with DoC. These tools are now being used to detect residual and covert awareness in behaviourally non-responsive patients with an acquired severe brain injury and predict which patients are likely to recover. Despite endorsement of advanced imaging by multiple clinical bodies, widespread implementation of imaging techniques such as functional MRI (fMRI), electroencephalography (EEG), and positron emission tomography (PET) in both acute and prolonged disorders of consciousness patients has been hindered by perceived costs, technological barriers, and lack of expertise needed to acquire, interpret, and implement these methods. In this review we provide a comprehensive overview of neuroimaging in DoC, the different technical approaches employed (i.e. fMRI, EEG, PET), the imaging paradigms used (active, passive, resting state) and the types of inferences that have been made about residual cortical function based on those paradigms (e.g., perception, awareness, communication). Next, we outline how these barriers might be overcome, discuss which select patients stand to benefit the most from these neuroimaging techniques, and consider when during their clinical trajectory imaging tests are likely to be most useful. Moreover, we make recommendations that will help clinicians decide which advanced imaging technologies and protocols are likely to be most appropriate in any particular clinical case. Finally, we describe how these techniques can be implemented in routine clinical care to augment current clinical tools and outline future directions for the field as a whole.
AbstractAs the world's population ages, more and more people are expected to suffer from age-related diseases. Biological aging markers derived from DNA methylation and brain structure show promise in predicting health outcomes. Understanding the relationship between these biomarkers can promote the development of effective health interventions.In a sample of 254 participants from the Netherlands Twin Register (20-84 years), we investigated associations between DNA methylation age acceleration based on five epigenetic biomarkers (Hannum, Horvath, PhenoAge, GrimAge, and DunedinPACE) and brain age acceleration based on neuroimaging (brainageR). Furthermore, we applied bivariate twin models to examine the contribution of genetic and environmental factors to the associations (cross-twin cross-trait correlations and within monozygotic-twin pair differences).We observed relationships with brain age acceleration for DNA methylation age acceleration based on the Hannum and GrimAge clocks that were supported by within MZ twin pair difference modelling. Cross-twin cross-trait modelling confirmed a non-shared environmental etiology.Twin analyses highlight the importance of the environment in accelerated aging, raising the possibility for interventions such as lifestyle modification.
AbstractCognitive impairment is a major contributor to the burden in Parkinson’s disease and dementia with Lewy bodies, both of which make up the Lewy body disease spectrum, with dementia affecting up to 80% of patients over the course of the disease. Macroatrophy and microstructural neurodegenerative alterations are typically assessed separately in MRI, although neuropathologically they represent the same mechanism - the loss of functional tissue. To gain a deeper insight into the differential impact of neurodegeneration in the basal forebrain and hippocampus on cognition, we have developed a combined volumetric-mesoscopic approach to more comprehensively quantify the extent of neurodegeneration. This approach might facilitate a more profound understanding of cognitive decline.We report a retrospective analysis of MRI data from 147 patients with Lewy body disease (Parkinson’s disease with normal cognition=50, with mild cognitive impairment=59, with dementia=25 and 13 patients with dementia with Lewy bodies) and 30 healthy controls. Neurodegeneration of the basal forebrain and hippocampus was quantified by assessing the total macrostructural volume and microstructural metrics. Additionally, these parameters were combined to evaluate the potential of the functional volume for capturing the coinciding pathophysiological processes. The extent of neurodegeneration was compared between healthy controls, patients with normal cognition, mild impaired cognition, and dementia. Furthermore, the integrity of the basal forebrain and hippocampus was tested for associations with subdomains of cognitive performance as assessed with the Mattis Dementia Rating Scale 2.Our results revealed significant macro- and microstructural degeneration in the basal forebrain and hippocampus in patients with Parkinson's disease dementia and dementia with Lewy bodies when compared to healthy controls or Lewy body disease without dementia. Combining volumetric and microstructural metrics to calculate the functional volume provided the strongest effects across cognitive function in Lewy body disease. Moreover, in a combined model of basal forebrain and hippocampus, degeneration of the basal forebrain only was significantly associated with impaired initiation (p=0.003) and trend-level linked to attention (p=0.06), whereas hippocampal integrity significantly determined memory (p=0.005) and conceptualization at trend level (p=0.06).Combining macro- and microstructural techniques to investigate the functional volume of the basal forebrain and hippocampus revealed that basal forebrain and hippocampal integrity is altered only in LBD with dementia but not in LBD with normal cognition or mild cognitive impairment. Moreover, the basal forebrain and hippocampus were differentially associated with distinct neurocognitive domains, thus providing an intriguing biomarker for neurocognitive staging in LBD or individualized treatment concepts.
AbstractTuberous sclerosis complex (TSC) is a phenotypically heterogeneous autosomal dominant epilepsy, neuropsychiatric, and tumoral predisposition disease, occurring due to germline variants in the TSC1 or TSC2 genes. Despite an improving understanding of the varied phenotypes TSC may present with, there remains an incomplete understanding of the disease trajectory and genotype-phenotype relationship in this disorder. We sought to examine whether an unbiased clustering approach could uncover subgroups of disease trajectories in TSC and enhance understanding of genotype-phenotype correlation.In this observational, prospective, multicentre natural history cohort of patients with confirmed diagnosis of TSC (TSC Alliance Natural History Database), data collected from 2006 - 2022 was used to identify groups of co-occurring phenotypes. This was a multicentre study involving 18 TSC clinical network centres in the US. 947 individuals were included, all of whom had a clinical diagnosis of tuberous sclerosis complex. Each patient was required to have complete characterization of 29 phenotype features associated with TSC. The primary outcomes were consensus clusters of clinical features defining subgroups of patients with TSC and their association with genotype.947 individuals (50% male) across the TSC Alliance Natural History Database were included in this study, and 29 clinical features were used to define clusters of phenotypes to define disease trajectories. Four reproducible and distinct disease subgroups were identified: angiomyolipoma-predominant TSC (cluster 1), TSC with infantile spasms (cluster 2), neuropsychiatric TSC (cluster 3), and a milder phenotype of TSC (cluster 4). Variants in the rho domain of hamartin and the TSC1 binding domain of tuberin preferentially associated with cluster 1, with increased likelihood of angiomyolipomas, dermatologic findings, and subependymal giant cell astrocytoma.Four distinct disease subgroups exist in TSC and differentially associate with variant location, informing deep genotype-phenotype correlation in TSC with potential impact in personalizing disease surveillance, treatment, and clinical trial endpoint choice. Additional prospective data are needed to confirm these findings.
AbstractMutations in myelin protein zero (MPZ) are generally associated with Charcot-Marie-Tooth type 1B (CMT1B) disease, one of the most common forms of demyelinating neuropathy. Pathogenesis of some MPZ mutants, such as S63del and R98C, involves the misfolding and retention of MPZ in the endoplasmic reticulum (ER) of myelinating Schwann cells. To cope with proteotoxic ER-stress, Schwann cells mount an unfolded protein response (UPR) characterized by activation of the PERK, ATF6 and IRE1α/XBP1 pathways. Previous results showed that targeting the PERK UPR pathway mitigates neuropathy in mouse models of CMT1B; however, the contributions of other UPR pathways in disease pathogenesis remains poorly understood.Here, we probe the importance of the IRE1α/XBP1 signalling during normal myelination and in CMT1B. In response to ER stress, IRE1α is activated to stimulate the non-canonical splicing of Xbp1 mRNA to generate spliced Xbp1 (Xbp1s). This results in the increased expression of the adaptive transcription factor XBP1s, which regulates the expression of genes involved in diverse pathways including ER proteostasis. We generated mouse models where Xbp1 is deleted specifically in Schwann cells, preventing XBP1s activation in these cells. We observed that Xbp1 is dispensable for normal developmental myelination, myelin maintenance and remyelination after injury. However, Xbp1 deletion dramatically worsens the hypomyelination and the electrophysiological and locomotor parameters observed in young and adult CMT1B neuropathic animals. RNAseq analysis suggested that XBP1s exerts its adaptive function in CMT1B mouse models in large part via the induction of ER proteostasis genes. Accordingly, the exacerbation of the neuropathy in Xbp1 deficient mice was accompanied by upregulation of ER-stress pathways and of IRE1-mediated RIDD signaling in Schwann cells, suggesting that the activation of XBP1s via IRE1 plays a critical role in limiting mutant protein toxicity and that this toxicity cannot be compensated by other stress responses. Schwann cell specific overexpression of XBP1s partially re-established Schwann cell proteostasis and attenuated CMT1B severity in both the S63del and R98C mouse models. In addition, the selective, pharmacologic activation of IRE1α/XBP1 signaling ameliorated myelination in S63del dorsal root ganglia explants.Collectively, these data show that XBP1 has an essential adaptive role in different models of proteotoxic CMT1B neuropathy and suggest that activation of the IRE1α/XBP1 pathway may represent a therapeutic avenue in CMT1B and possibly for other neuropathies characterized by UPR activation.
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Dynamic processes involving biomolecules are essential for the function of the cell. Here, we introduce an integrative method for computing models of these processes based on multiple heterogeneous sources of information, including time-resolved experimental data and physical models of dynamic processes. First, for each time point, a set of coarse models of compositional and structural heterogeneity is computed (heterogeneity models). Second, for each heterogeneity model, a set of static integrative structure models is computed (a snapshot model). Finally, these snapshot models are selected and connected into a series of trajectories that optimize the likelihood of both the snapshot models and transitions between them (a trajectory model). The method is demonstrated by application to the assembly process of the human nuclear pore complex in the context of the reforming nuclear envelope during mitotic cell division, based on live-cell correlated electron tomography, bulk fluorescence correlation spectroscopy–calibrated quantitative live imaging, and a structural model of the fully assembled nuclear pore complex. Modeling of the assembly process improves the model precision over static integrative structure modeling alone. The method is applicable to a wide range of time-dependent systems in cell biology and is available to the broader scientific community through an implementation in the open sourceIntegrative Modeling Platform (IMP)software.
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The medial prefrontal cortex (mPFC) and hippocampus are critical for memory retrieval, decision making, and emotional regulation. While ventral CA1 (vCA1) shows direct and reciprocal connections with mPFC, dorsal CA1 (dCA1) forms indirect pathways to mPFC, notably via the thalamic reuniens nucleus (Re). Neuroanatomical tracing has documented structural connectivity of this indirect pathway through Re however, its functional operation is largely unexplored. Here, we used in vivo and in vitro electrophysiology along with optogenetics to address this question. Whole-cell patch-clamp recordings in acute mouse brain slices revealed both monosynaptic excitatory responses and disynaptic feedforward inhibition at Re–mPFC synapses. However, we also identified a prolonged excitation of mPFC by Re. These early monosynaptic and late recurrent components are in marked contrast to the primarily feedforward inhibition characteristic of thalamic inputs to the neocortex. Local field potential recordings in mPFC brain slices revealed prolonged synaptic activity throughout all cortical lamina upon Re activation, with the late excitation enhanced by blockade of parvalbumin neurons and GABAARs. In vivo Neuropixels recordings in head-fixed awake mice revealed a similar prolonged excitation of mPFC units by Re activation. In summary, Re output produces recurrent feedforward excitation within mPFC suggesting a potent amplification system in the Re–mPFC network. This may facilitate amplification of dCA1->mPFC signals for which Re acts as the primary conduit, as there is little direct connectivity. In addition, the capacity of mPFC neurons to fire bursts of action potentials in response to Re input suggests that these synapses have a high gain.
The problem of combiningP-values is an old and fundamental one, and the classic assumption of independence is often violated or unverifiable in many applications. There are many well-known rules that can combine a set of arbitrarily dependentP-values (for the same hypothesis) into a singleP-value. We show that essentially all these existing rules can be strictly improved when theP-values are exchangeable, or when external randomization is allowed (or both). For example, we derive randomized and/or exchangeable improvements of well-known rules like “twice the median” and “twice the average,” as well as geometric and harmonic means. ExchangeableP-values are often produced one at a time (for example, under repeated tests involving data splitting), and our rules can combine them sequentially as they are produced, stopping when the combinedP-values stabilize. Our work also improves rules for combining arbitrarily dependentP-values, since the latter becomes exchangeable if they are presented to the analyst in a random order. The main technical advance is to show that all existing combination rules can be obtained by calibrating theP-values to e-values (using anα-dependent calibrator), averaging those e-values, converting to a level-αtest using Markov’s inequality, and finally obtainingP-values by combining this family of tests; the improvements are delivered via recent randomized and exchangeable variants of Markov’s inequality.
The daily cycle of photosynthetic primary production at the base of marine food webs is often limited by the availability of scarce nutrients. Microbial competition for these scarce resources can be alleviated insofar as the intensity of nutrient uptake and assimilation activities are distributed heterogeneously across organisms over periodic input cycles. Recent analysis of community transcriptional dynamics in the nitrogen-limited subtropical North Pacific gyre revealed evidence of temporal partitioning of nitrogen uptake and assimilation between eukaryotic phytoplankton, cyanobacteria, and heterotrophic bacteria over day-night cycles. Here, we present results from a Lagrangian metatranscriptomic time series survey in the Sargasso Sea and demonstrate temporally partitioned phosphorus uptake in this phosphorus-limited environment. In the Sargasso, heterotrophic bacteria, eukaryotic phytoplankton, and cyanobacteria express genes for phosphorus assimilation during the morning, day, and dusk, respectively. These results support the generality of temporal niche partitioning as an emergent mechanism that can structure uptake of limiting nutrients and facilitate coexistence of diverse microbes in open ocean ecosystems.
Active turbulence, or chaotic self-organized collective motion, is often observed in concentrated suspensions of motile bacteria and other systems of self-propelled interacting agents. To date, there is no fundamental understanding of how geometrical confinement orchestrates active turbulence and alters its physical properties. Here, by combining large-scale experiments, computer modeling, and analytical theory, we have identified a generic sequence of transitions occurring in bacterial suspensions confined in cylindrical wells of varying radii. With increasing the well’s radius, we observed that persistent vortex motion gives way to periodic vortex reversals, four-vortex pulsations, and then well-developed active turbulence. Using computational modeling and analytical theory, we have shown that vortex reversal results from the nonlinear interaction of the first three azimuthal modes that become unstable with the radius increase. The analytical results account for our key experimental findings. To further validate our approach, we reconstructed equations of motion from experimental data. Our findings shed light on the universal properties of confined bacterial active matter and can be applied to various biological and synthetic active systems.
At the end of their growth phase,Drosophilalarvae remodel their bodies, glue themselves to a substrate, and harden their cuticle in preparation for metamorphosis. This process—termed pupariation—is triggered by a surge in the hormone ecdysone. Substrate attachment is achieved by a pupariation subprogram called glue expulsion and spreading behavior (GSB). An epidermis-to-CNS Dilp8-Lgr3 relaxin signaling event that occurs downstream of ecdysone is critical for unlocking progression of the pupariation motor program toward GSB, but the factors and circuits acting downstream of Lgr3 signaling remain unknown. Here, using cell-type-specific RNA interference and behavioral monitoring, we identify Myoinhibiting peptide (Mip) as a neuromodulator of multiple GSB action components, such as tetanic contraction, peristaltic contraction alternation, and head-waving. Mip is required in a pair of brain descending neurons, which act temporally downstream of Dilp8-Lgr3 signaling. Mip modulates GSB via ventral nerve cord neurons expressing its conserved receptor, sex peptide receptor (SPR). Silencing of Mip descending neurons by hyperpolarization completely abrogates GSB, while their optogenetic activation at a restricted competence time window triggers GSB-like behavior. Hence, Mip descending neurons have at least two functions: to act as GSB command neurons and to secrete Mip to modulate GSB action components. Our results provide insight into conserved aspects of Mip-SPR signaling in animals, reveal the complexity of GSB control, and contribute to the understanding of how multistep innate behaviors are coordinated in time and with other developmental processes through command neurons and neuropeptidergic signaling.
Deforestation frequently accompanies poverty, yet various antipoverty programs in many countries have exhibited mixed results in addressing deforestation. Poverty Alleviation Resettlement (PAR) stands out as one of the few government-led resettlement programs designed to alleviate poverty, offering comprehensive follow-up support for quality of life and employment after relocation. Our study uncovered empirical evidence of the PAR program’s impact on forest quality. Through a multiperiod difference-in-differences analysis of remote sensing and household survey data, we found that the PAR program significantly curbed deforestation in the participating counties and reduced forest-clearing activities among the resettled households, even those relocating to rural villages. Mechanism analysis revealed that the program discouraged deforestation by enhancing market accessibility, fostering nonfarm employment opportunities, and elevating income levels. The study underscores that altering livelihood strategies and lifestyles is essential for resettlement programs to effectively mitigate ecological degradation.
We study the driven-dissipative Bose-Hubbard model with an all-to-all hopping term in the system Hamiltonian, while subject to incoherent pumping and decay from the environment. This system is naturally probed in several recent experiments on excitons in WS2/WSe2moiré systems, as well as quantum simulators. By positing a particular form of coupling to the environment, we derive the Lindblad jump operators and show that, in certain limits, the system admits a closed-form expression for the steady-state density matrix. Away from the exactly solvable regions, the steady state can be obtained numerically for 100s to 1,000s of sites. We study the nonequilibrium phase diagram and phase transitions, which qualitatively matches the equilibrium phase diagram, agreeing with the intuition that increasing the intensity of the light is equivalent to changing the bosonic chemical potential. However, the steady states are far from thermal states, and the nature of the phase transitions is changed.
Dopamine (DA) signals to the striatum play critical roles in shaping and sustaining stimulus-reward associations. In primates, however, the dynamics of the DA signals remain unknown since conventional methods are not necessarily appropriate in terms of the spatiotemporal resolution or chemical specificity sufficient for detecting the DA signals. In our study, fiber photometry with a fluorescent DA sensor was employed to identify reward-related DA transients in the monkey striatum. This technique, which directly monitors local DA release, reveals a reward prediction error signal in the anterior putamen originating from midbrain DA neurons. Further, DA transients in the head of the caudate nucleus exhibit a value-based response to reward-predicting stimuli. These signals have been found to arise from two separate groups of DA neurons in the substantia nigra pars compacta. The present results demonstrate that fluorescence DA monitoring is applicable to detect DA signals in the primate striatum for investigating their roles.
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Mixed-species plantations are increasingly recognized for their potential to maintain forest biodiversity and soil health; however, a comprehensive assessment of their global effectiveness is lacking. To fill this knowledge gap, we conducted a meta-analysis of 7,045 paired observations between mixed-species and monoculture plantations, derived from 311 studies across diverse forest ecosystems worldwide. Our results show that mixed-species plantations significantly increased understory plant biomass, cover, and species richness by 32.6%, 55.4%, and 32.2%, respectively, compared to monocultures. Furthermore, the Shannon and Pielou diversity indices increased by 28.2% and 8.6%, respectively, and the Simpson index increased by 9.6%. When understory shrub and herbaceous species were considered separately, species mixing had significantly positive effects on shrub diversity but had no effect on herbaceous diversity. Moreover, mixed-species plantations markedly improved soil physical and chemical properties compared to monocultures. These improvements include increases in soil nutrient content (9.6 to 17.8%) and nutrient availability (14.7 to 33.5%), soil microbial biomass (17.2 to 28.8%), and soil carbon sequestration (7.2 to 19.9%). These enhancements were particularly pronounced in plantations that included legumes. Our findings reveal that the benefits of species mixing are influenced by climatic conditions, geographic location, and stand age, with the most substantial effects observed in temperate regions and mature stands. This study underscores the critical role of mixed-species plantations in promoting sustainable forest management and mitigating the ecological limitations of monocultures.
Neuropathic pain is a debilitating chronic condition mainly caused by peripheral nerve injury. However, the cellular and molecular mechanisms underlying this condition remain unclear. Transient receptor potential canonical 3 (TRPC3), a TRP channel that is activated by downstream of the Gq-phospholipase C (PLC) axis, is expressed in the somatosensory system. Therefore, the present study investigated its pathophysiological role in neuropathic pain following peripheral nerve injury. Here, partial sciatic nerve ligation (pSNL) elicited mechanical and thermal hypersensitivity in wild-type mice, which was suppressed in TRPC3-KO mice. In situ hybridization revealed that TRPC3 is predominantly expressed in neurons in the spinal dorsal horn. Furthermore, spinal dorsal horn neuron-specific downregulation using miRNA attenuated pSNL-induced mechanical hypersensitivity. Spinal TRPC3 activation elicited acute mechanical hypersensitivity. Moreover, its genetic ablation reduced the mechanical hypersensitivity caused by spinal NK1R or PLC activation. These findings demonstrate that TRPC3 in spinal dorsal horn neurons facilitates the development of neuropathic pain. Therefore, TRPC3 may be a promising therapeutic target for neuropathic pain caused by peripheral nerve injury.
We investigate the mechanics of two asymmetric ribbons bound at one end and pulled apart at the other ends. We characterize the elastic junction near the bonding and conceptualize it as a bending boundary layer. While the size of this junction decreases with the pulling force, we observe the surprising existence of the binding angle as a macroscopic signature of the bending stiffnesses. Our results thus challenge the standard assumption of neglecting bending stiffness of thin shells at large tensile loading. In addition, we show how the rotational response of the structure exhibits a nonlinear and universal behavior regardless of the ratio of asymmetry. Leveraging the independence of the binding angle to the pulling force, we finally introduce theλ-test—a visual measurement technique to characterize membranes through simple mechanical coupling.
Metamorphic proteins switch reversibly between two differently folded states under a variety of environmental conditions. Their identification and prediction are gaining attention, but the fundamental physicochemical basis for fold switching remains poorly understood. In this Perspective article, we address this problem by surveying the landscape of well-characterized metamorphic proteins and noting that a significant fraction of them display temperature sensitivity. We then make the case that the dependence on temperature, in particular cold-denaturation effects, is likely to be an underlying property of many metamorphic proteins regardless of their ultimate triggering mechanisms, especially those with a single domain. The argument is supported by rigorous analysis of hydrophobic effects in each well-characterized metamorphic protein pair and a description of how these parameters relate to temperature. The conclusion discusses the relevance of these insights to a better understanding of prediction, evolution, and de novo design strategies for metamorphic proteins.
Recent findings show that stereotyped movement sequences (habits) need the cortex in the learning phase, but after learning, the cortex can be inactivated, and the movement still be performed flawlessly. The motor program is dependent on the sensorimotor part of the dorsolateral striatum (DLS) and on synaptic plasticity in the thalamostriatal synapses. New findings from several laboratories have revealed a highly precise spatially interactive organization within the basal ganglia [DLS, substantia nigra pars reticulata (SNr), and the thalamostriatal parafascicular nucleus (PF)] and with precise input from the cortex. The DLS-SNr-PF-DLS loop is subdivided into many parallel loops. I now propose that these parallel loops can act to reinforce the activity of the different striatal projection neurons in the DLS that take part and that the synaptic transmission in DLS becomes potentiated each time the motor sequence is performed successfully, if rewarded through a dopamine burst. It is argued that after learning the DLS-SNr-PF-DLS loop can operate in isolation.
We study how self-organization in systems showing complex spatiotemporal dynamics can increase ecosystem resilience. We consider a general simple model that includes positive feedback as well as negative feedback mediated by an inhibitor. We apply this model toPosidonia oceanicameadows, where positive and negative feedbacks are well documented, and there is empirical evidence of the role of sulfide accumulation, toxic for the plant, in driving complex spatiotemporal dynamics. We describe a progressive transition from homogeneous meadows to extinction through dynamical regimes that allow the ecosystem to avoid the typical ecological tipping points of homogeneous vegetation covers. A predictable sequence of distinct dynamical regimes is observed as mortality is continuously increased: turbulent regimes, formation of spirals and wave trains, and isolated traveling pulses or expanding rings, the latter being a harbinger of ecosystem collapse, however far beyond the tipping point of the homogeneous cover. The model used in this paper is general, and the results can be applied to other plant–soil spatially extended systems, regardless of the mechanisms behind negative and positive feedbacks.
The importance of macrophages in kidney diseases has been well established; however, the mechanisms underlying the infiltration of macrophages into injured kidneys are not well understood. RGMb is a member of the repulsive guidance molecule (RGM) family. RGMb can be expressed on the cell surface but a large portion of RGMb is localized intracellularly. Among various immune cell types, macrophages express the highest levels of RGMb, but the biological functions of RGMb in macrophages remain largely unknown. We find that RGMb promoted macrophage migration in vitro and that in vivo, RGMb enhanced infiltration of macrophages into injured kidneys and aggravated kidney inflammation and injury in mice. Mechanistically, RGMb bound to TAB1 inside the cell and facilitated the interaction between TRAF6 ubiquitin ligase and TAB1, thereby promoting TRAF6-mediated K63-linked polyubiquitination and phosphorylation of TAK1, followed by increased αTAT1 phosphorylation and α-tubulin acetylation. The resulting changes in the cytoskeleton promoted macrophage migration in vitro and in vivo. Deletion of Rgmb in macrophages markedly reduced TAK1 phosphorylation, αTAT1 phosphorylation, and α-tubulin acetylation and attenuated macrophage infiltration, renal inflammation, tubular injury, and interstitial fibrosis during kidney injury. Our results suggest that macrophage RGMb promotes kidney disease by increasing macrophage infiltration via the TRAF6-TAB1-TAK1/αTAT1/α-tubulin cascade.
As infants grow, they develop greater attentional control during interactions with others, shifting from patterns of attention primarily driven by caregivers (exogenous) to those that are also self-directed (endogenous). The ability to endogenously control attention during infancy is thought to reflect ongoing brain development and is influenced by patterns of joint attention between infant and caregiver. However, whether measures of infant attentional control and caregiver behavior during infant–caregiver interactions relate to patterns of infant brain activity is unknown and key for informing developmental models of attentional control. Using data from 43 infant–caregiver dyads, we quantified patterns of visual attention with dyadic, head-mounted eye tracking during infant–caregiver play and associated them with the duration of infant EEG microstate D/4 measured during rest. Importantly, microstate D/4 is a scalp potential topography thought to reflect the organization and function of attention-related brain networks. We found that microstate D/4 associated positively with infant-led joint attention rate but did not associate with caregiver-led joint attention rate, suggesting that infant-led coordination of joint attention during play may be critical for the neurobiological development of attentional control, or vice versa. Further, we found that microstate D/4 associated negatively with infant attention shift rate and positively with infant sustained attention duration, suggesting that increased stability of microstate D/4 may reflect maturation of attentional control and its underlying neural substrates. Together, our findings provide insights into how infant attentional control abilities and infant–caregiver visual behavior during play are associated with the spatial and temporal dynamics of infant brain activity.
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Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, pannus formation, and progressive joint destruction. The inflammatory milieu in RA drives endothelial cell activation and upregulation of adhesion molecules, thus facilitating leukocyte infiltration into the synovium. Reelin, a circulating glycoprotein previously implicated in endothelial activation and leukocyte recruitment in diseases such as atherosclerosis and multiple sclerosis, has emerged as a potential upstream regulator of these processes. However, its role in RA pathogenesis remains poorly understood. Here, we demonstrate that Reelin levels are markedly elevated in the plasma of both RA patients and mouse models of arthritis, with higher concentrations correlating with greater disease severity. Genetic deletion of the Reelin receptor Apoer2 conferred significant protection against serum transfer arthritis (STA), underscoring the relevance of this pathway in disease progression. Furthermore, therapeutic inhibition of Reelin using the CR-50 antibody yielded robust anti-inflammatory effects in multiple preclinical arthritis models, including STA, K/BxN, and collagen-induced arthritis. Notably, CR-50 treatment not only reduced leukocyte infiltration and synovial inflammation but also mitigated pannus formation. Importantly, these benefits were achieved without the gastrointestinal side effects commonly associated with nonsteroidal anti-inflammatory drugs like diclofenac. Our findings position Reelin as a proinflammatory endothelial biomarker and therapeutic target in RA. By modulating endothelial activation and leukocyte recruitment, anti-Reelin strategies offer an alternative approach to attenuate synovial inflammation and joint damage. These results provide a compelling rationale for further exploration of Reelin-targeted therapies as alternatives to conventional immunosuppressive treatments in RA and other chronic inflammatory diseases.
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Chronic infections with hepatitis E virus (HEV), especially those of genotype 3 (G3), frequently lead to liver fibrosis and cirrhosis in patients. However, the causation and mechanism of liver fibrosis triggered by chronic HEV infection remain poorly understood. Here, we found that the viral multiple-domain replicase (ORF1) undergoes unique ubiquitin–proteasomal processing leading to formation of theHEV-DerivedSMADActivator (HDSA), a viral polypeptide lacking putative helicase and RNA polymerase domains. The HDSA is stable, non-HSP90-bound, localizes to the nucleus, and is abundant in G3 HEV-infected hepatocytes of various origins. Markedly, the HDSA in hepatocytes potentiates the fibrogenic TGF-β/SMAD pathway by forming compact complexes with SMAD3 to facilitate its promoter binding and coactivator recruitment, leading to significant fibrosis in HEV-susceptible gerbils. Virus infection–induced liver fibrosis in HEV-susceptible gerbils could be prevented by mutating the residues P989C, A990C, and A991C (PAA-3C) within ORF1, which are required for proteasomal processing. Thus, we have identified a viral protein derived from host proteasomal processing, defined its notable role in liver fibrosis and highlighted the nature of an unanticipated host–HEV interaction that facilitates hepatitis E pathogenesis.
CRISPR-Cas9 systems have revolutionized biotechnology, creating diverse new opportunities for biomedical research and therapeutic genome and epigenome editing. Despite the abundance of bacterial CRISPR-Cas9 systems, relatively few are effective in human cells, limiting the overall potential of CRISPR technology. To expand the CRISPR-Cas toolbox, we characterized a set of type II CRISPR-Cas9 systems from select bacterial genera and species encoding diverse Cas9s. Four systems demonstrated robust and specific gene repression in human cells when used as nuclease-null dCas9s fused with a KRAB domain and were also highly active nucleases in human cells. These systems have distinct protospacer adjacent motifs (PAMs), including AT-rich motifs and sgRNA features orthogonal to the commonly usedStaphylococcus aureusandStreptococcus pyogenesCas9s. Additionally, we assessed gene activation when fused with the p300 catalytic domain. Notably,S. uberisCas9 performed competitively against benchmarks with promising repression, activation, nuclease, and base editing activity. This study expands the CRISPR-Cas9 repertoire, enabling effective genome and epigenome editing for diverse applications.
The cytoskeleton is crucial for cell organization and movement. In Eukaryotes, it largely consists of the protein actin, that forms a double-stranded linear filamentous structure in the presence of ATP and disassemble upon ATP hydrolysis. Bacteria also possess actin homologs, that drive fundamental cellular processes, including cell division, shape maintenance, and DNA segregation. Like eukaryotic actin, bacterial actins assemble into dynamic polymers upon ATP binding, however variation in interactions between strands gives rise to striking diversity of filament architectures. Here, we report a family of bacterial actins of unknown function, conserved among theVerrucomicrobiotaphylum, which assembles into a unique tubular structure in the presence of ATP. A cryo-EM structure of the filaments reveals that it consists of three strands, unlike other described bacterial actin structures. This architecture provides further insights into the organization of actin-like filaments and has implications for understanding the diversity and evolution of the bacterial cytoskeleton.
We evaluated the in vivo therapeutic efficacy and tolerability of BI-3406-mediated pharmacological inhibition of SOS1 in comparison to genetic ablation of this universal Ras-GEF in various KRAS-dependent experimental tumor settings. Contrary to the rapid lethality caused by SOS1 genetic ablation in SOS2KOmice, SOS1 pharmacological inhibition by its specific inhibitor BI-3406 did not significantly affect animal weight/viability nor cause noteworthy systemic toxicity. Allograft assays using different KRASmutcell lines showed that treatment with BI-3406 impaired RAS activation and RAS downstream signaling and decreased tumor burden and disease progression as a result of both tumor-intrinsic and -extrinsic therapeutic effects of the drug. Consistent with prior genetic evidence and the KRASmutallografts assays in immunocompromised mice, our analyses using an in vivo model of KRASG12D-driven lung adenocarcinoma (LUAD) in immunocompetent mice showed that single, systemic BI-3406 treatment impaired tumor growth and downmodulated protumorigenic components of the tumor microenvironment comparably to SOS1 genetic ablation or to treatment with the specific KRASG12Dinhibitor MRTX1133. Furthermore, markedly stronger, synergistic antitumor effects were observed upon concomitant treatment with BI-3406 and MRTX1133 in the same in vivo LUAD mouse model. Our data confirm SOS1 as an actionable therapy target in RAS-dependent cancers and suggest that BI-3406 treatment may yield clinical benefit both as monotherapy or as a potential combination partner for multiple RAS-targeting strategies.
Currently, most cell or tissue transplantations using induced pluripotent stem cells (iPSCs) are anticipated to involve allogeneic iPSCs. However, the immunological properties of iPSCs in an allogeneic setting are not well understood. We previously established a mouse transplantation model of MHC-compatible/minor antigen-mismatched combinations, assuming a hypoimmunogenic iPSC-setting. Here, we found that iPSCs subcutaneously inoculated into MHC-compatible allogeneic host mice resisted rejection and formed teratomas without immunosuppressant administration. Notably, when skin grafts were transplanted onto hosts more than 40 d after the initial iPSCs inoculation, only the skin of the same strain as the initial iPSCs was engrafted. Therefore, donor-specific immune tolerance was induced by a single iPSC inoculation. Diverse analyses, including single-cell RNA-sequencing after transplantation, revealed an increase in regulatory T cell (Treg) population, particularly CD25+CD103+effector Tregs within the teratoma and skin grafts. The removal of CD25+or Foxp3+cells suppressed the increase in effector Tregs and disrupted graft acceptance, indicating the importance of these cells in the establishment of immune tolerance. Within the teratoma, we observed an increase in TGF-β2 levels, suggesting an association with the increase in effector Tregs. Our results provide important insights for future applications of allogeneic iPSC-based cell or tissue transplantation.
Low-energy excitations play a key role in all condensed-matter systems, yet there is limited understanding of their nature in glasses, where they correspond to local rearrangements of groups of particles. Here, we introduce an algorithm to systematically uncover these excitations up to the activation energy scale relevant to structural relaxation. We use it in a model system to measure the density of states on a scale never achieved before, confirming that this quantity shifts to higher energy under cooling, precisely as the activation energy does. Second, we show that the excitations’ energetic and spatial features allow one to predict with great accuracy the dynamic propensity, i.e., the location of future relaxation dynamics. Finally, we find that excitations have a primary field whose properties, including the displacement of the most mobile particle, scale as a power-law of their activation energy and are independent of temperature. Additionally, they exhibit an outer deformation field that depends on the material’s stability and, therefore, on temperature. We build a scaling description of these findings. Overall, our analysis supports that excitations play a crucial role in regulating relaxation dynamics near the glass transition, effectively suppressing the transition to dynamical arrest predicted by mean-field theories while also being strongly influenced by it.
Nonlinear plasma physics problems are usually simulated through comprehensive modeling of phase space. The extreme computational cost of such simulations has motivated the development of multi-moment fluid models. However, a major challenge has been finding a suitable fluid closure for these fluid models. Recent developments in physics-informed machine learning have led to a renewed interest in constructing accurate fluid closure terms. In this study, we take an approach that integrates kinetic physics from the first-principles Vlasov simulations into a fluid model (through the heat flux closure term) using the Fourier neural operator—a neural network architecture. Without resolving the phase space dynamics, this new fluid model is capable of capturing the nonlinear evolution of the Landau damping process that exactly matches the Vlasov simulation results. This machine learning–assisted new approach provides a computationally affordable framework that surpasses previous fluid models in accurately modeling the kinetic evolution of complex plasma systems.
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To navigate real-world listening conditions, the auditory system relies on the integration of multiple sources of information. However, to avoid inappropriate cross-talk between inputs, highly connected neural systems need to strike a balance between integration and segregation. Here, we develop a novel approach to examine how repeated neurochemical modules in the mouse inferior colliculus lateral cortex (LC) allow controlled integration of its multimodal inputs. The LC had been impossible to study via imaging because it is buried in a sulcus. Therefore, we coupled two-photon microscopy with the use of a microprism to reveal the first-ever sagittal views of the LC to examine neuronal responses with respect to its neurochemical motifs under anesthetized and awake conditions. This approach revealed marked differences in the acoustic response properties of LC and neighboring non-lemniscal portions of the inferior colliculus. In addition, we observed that the module and matrix cellular motifs of the LC displayed distinct somatosensory and auditory responses. Specifically, neurons in modules demonstrated primarily offset responses to acoustic stimuli with enhancement in responses to bimodal stimuli, whereas matrix neurons showed onset response to acoustic stimuli and suppressed responses to bimodal stimulation. Thus, this new approach revealed that the repeated structural motifs of the LC permit functional integration of multimodal inputs while retaining distinct response properties.
Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however, few studies have investigated its role in neurodegenerative processes such as Alzheimer’s disease (AD). Here, we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in humans, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients.
Juvenile hormone (JH) is important to maintain insect larval status; however, its cell membrane receptor has not been identified. Using the lepidopteran insectHelicoverpa armigera(cotton bollworm), a serious agricultural pest, as a model, we determined that receptor tyrosine kinases (RTKs) cadherin 96ca (CAD96CA) and fibroblast growth factor receptor homologue (FGFR1) function as JH cell membrane receptors by their roles in JH-regulated gene expression, larval status maintaining, rapid intracellular calcium increase, phosphorylation of JH intracellular receptor MET1 and cofactor Taiman, and high affinity to JH III. Gene knockout ofCad96caandFgfr1by CRISPR/Cas9 in embryo and knockdown in various insect cells, and overexpression of CAD96CA and FGFR1 in mammalian HEK-293T cells all supported CAD96CA and FGFR1 transmitting JH signal as JH cell membrane receptors.
Natural killer (NK) cells recognize target cells through germline-encoded activation and inhibitory receptors enabling effective immunity against viruses and cancer. The Ly49 receptor family in the mouse and killer immunoglobin-like receptor family in humans play a central role in NK cell immunity through recognition of major histocompatibility complex class I (MHC-I) and related molecules. Functionally, these receptor families are involved in the licensing and rejection of MHC-I-deficient cells through missing-self. The Ly49 family is highly polymorphic, making it challenging to detail the contributions of individual Ly49 receptors to NK cell function. Herein, we showed mice lacking expression of all Ly49s were unable to reject missing-self target cells in vivo, were defective in NK cell licensing, and displayed lower KLRG1 on the surface of NK cells. Expression of Ly49A alone on an H-2Ddbackground restored missing-self target cell rejection, NK cell licensing, and NK cell KLRG1 expression. Thus, a single inhibitory Ly49 receptor is sufficient to license NK cells and mediate missing-self in vivo.
Historically, the creation of the parasympathetic division of the autonomic nervous system of the vertebrates is inextricably linked to the unification of the cranial and sacral autonomic outflows. There is an intriguing disproportion between the entrenchment of the notion of a ‘cranio-sacral’ pathway, which informs every textbook schematic of the autonomic nervous system since the early XXthcentury, and the wobbliness of its two roots: an anatomical detail overinterpreted by Walter Holbrook Gaskell (the ‘gap’ between the lumbar and sacral outflows), on which John Newport Langley grafted a piece of physiology (a supposed antagonism of these two outflows on external genitals), repeatedly questioned since, to little avail. I retrace the birth of a flawed scientific concept (the cranio-sacral outflow) and the way in which it ossified instead of dissipated. Then, I suggest that the critique of the ‘cranio-sacral outflow’ invites, in turn, a radical deconstruction of the very notion of a ‘parasympathetic’ outflow, and a more realistic description of the autonomic nervous system.
Juvenile hormone (JH) is important to maintain insect larval status; however, its cell membrane receptor has not been identified. Using the lepidopteran insectHelicoverpa armigera(cotton bollworm), a serious agricultural pest, as a model, we determined that receptor tyrosine kinases (RTKs) cadherin 96ca (CAD96CA) and fibroblast growth factor receptor homologue (FGFR1) function as JH cell membrane receptors by their roles in JH-regulated gene expression, larval status maintaining, rapid intracellular calcium increase, phosphorylation of JH intracellular receptor MET1 and cofactor Taiman, and high affinity to JH III. Gene knockout ofCad96caandFgfr1by CRISPR/Cas9 in embryo and knockdown in various insect cells, and overexpression of CAD96CA and FGFR1 in mammalian HEK-293T cells all supported CAD96CA and FGFR1 transmitting JH signal as JH cell membrane receptors.
Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however, few studies have investigated its role in neurodegenerative processes such as Alzheimer’s disease (AD). Here, we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in humans, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients.
Natural killer (NK) cells recognize target cells through germline-encoded activation and inhibitory receptors enabling effective immunity against viruses and cancer. The Ly49 receptor family in the mouse and killer immunoglobin-like receptor family in humans play a central role in NK cell immunity through recognition of major histocompatibility complex class I (MHC-I) and related molecules. Functionally, these receptor families are involved in the licensing and rejection of MHC-I-deficient cells through missing-self. The Ly49 family is highly polymorphic, making it challenging to detail the contributions of individual Ly49 receptors to NK cell function. Herein, we showed mice lacking expression of all Ly49s were unable to reject missing-self target cells in vivo, were defective in NK cell licensing, and displayed lower KLRG1 on the surface of NK cells. Expression of Ly49A alone on an H-2Ddbackground restored missing-self target cell rejection, NK cell licensing, and NK cell KLRG1 expression. Thus, a single inhibitory Ly49 receptor is sufficient to license NK cells and mediate missing-self in vivo.
Mycobacterium tuberculosis(Mtb) infection of macrophages reprograms cellular metabolism to promote lipid retention. While it is clearly known that intracellularMtbutilize host-derived lipids to maintain infection, the role of macrophage lipid processing on the bacteria’s ability to access the intracellular lipid pool remains undefined. We utilized a CRISPR-Cas9 genetic approach to assess the impact of sequential steps in fatty acid metabolism on the growth of intracellularMtb. Our analyses demonstrate that macrophages that cannot either import, store, or catabolize fatty acids restrictMtbgrowth by both common and divergent antimicrobial mechanisms, including increased glycolysis, increased oxidative stress, production of pro-inflammatory cytokines, enhanced autophagy, and nutrient limitation. We also show that impaired macrophage lipid droplet biogenesis is restrictive toMtbreplication, but increased induction of the same fails to rescueMtbgrowth. Our work expands our understanding of how host fatty acid homeostasis impactsMtbgrowth in the macrophage.
Virion Infectivity Factor (Vif) of the Human Immunodeficiency Virus type 1 (HIV-1) targets and degrades cellular APOBEC3 proteins, key regulators of intrinsic and innate antiretroviral immune responses, thereby facilitating HIV-1 infection. While Vif’s role in degrading APOBEC3G is well-studied, Vif is also known to cause cell cycle arrest, but the detailed nature of Vif’s effects on the cell cycle has yet to be delineated. In this study, we employed high-temporal resolution single-cell live imaging and super-resolution microscopy to monitor individual cells during Vif-induced cell cycle arrest. Our findings reveal that Vif does not affect the G2/M boundary as previously thought. Instead, Vif triggers a unique and robust pseudo-metaphase arrest, distinct from the mild prometaphase arrest induced by Vpr. During this arrest, chromosomes align properly and form the metaphase plate, but later lose alignment, resulting in polar chromosomes. Notably, Vif, unlike Vpr, significantly reduces the levels of both Protein Phosphatase 1 (PP1) and 2 A (PP2A) at kinetochores, which regulate chromosome-microtubule interactions. These results unveil a novel role for Vif in kinetochore regulation that governs the spatial organization of chromosomes during mitosis.
RNA interference (RNAi) is a conserved pathway that utilizes Argonaute proteins and their associated small RNAs to exert gene regulatory function on complementary transcripts. While the majority of germline-expressed RNAi proteins reside in perinuclear germ granules, it is unknown whether and how RNAi pathways are spatially organized in other cell types. Here, we find that the small RNA biogenesis machinery is spatially and temporally organized duringCaenorhabditis elegansembryogenesis. Specifically, the RNAi factor, SIMR-1, forms visible concentrates during mid-embryogenesis that contain an RNA-dependent RNA polymerase, a poly-UG polymerase, and the unloaded nuclear Argonaute protein, NRDE-3. Curiously, coincident with the appearance of the SIMR granules, the small RNAs bound to NRDE-3 switch from predominantly CSR-class 22G-RNAs to ERGO-dependent 22G-RNAs. NRDE-3 binds ERGO-dependent 22G-RNAs in the somatic cells of larvae and adults to silence ERGO-target genes; here we further demonstrate that NRDE-3-bound, CSR-class 22G-RNAs repress transcription in oocytes. Thus, our study defines two separable roles for NRDE-3, targeting germline-expressed genes during oogenesis to promote global transcriptional repression, and switching during embryogenesis to repress recently duplicated genes and retrotransposons in somatic cells, highlighting the plasticity of Argonaute proteins and the need for more precise temporal characterization of Argonaute-small RNA interactions.
Dietary protein absorption in neonatal mammals and fishes relies on the function of a specialized and conserved population of highly absorptive lysosome-rich enterocytes (LREs). The gut microbiome has been shown to enhance absorption of nutrients, such as lipids, by intestinal epithelial cells. However, whether protein absorption is also affected by the gut microbiome is poorly understood. Here, we investigate connections between protein absorption and microbes in the zebrafish gut. Using live microscopy-based quantitative assays, we find that microbes slow the pace of protein uptake and degradation in LREs. While microbes do not affect the number of absorbing LRE cells, microbes lower the expression of endocytic and protein digestion machinery in LREs. Using transgene-assisted cell isolation and single cell RNA-sequencing, we characterize all intestinal cells that take up dietary protein. We find that microbes affect expression of bacteria-sensing and metabolic pathways in LREs, and that some secretory cell types also take up protein and share components of protein uptake and digestion machinery with LREs. Using custom-formulated diets, we investigated the influence of diet and LRE activity on the gut microbiome. Impaired protein uptake activity in LREs, along with a protein-deficient diet, alters the microbial community and leads to an increased abundance of bacterial genera that have the capacity to reduce protein uptake in LREs. Together, these results reveal that diet-dependent reciprocal interactions between LREs and the gut microbiome regulate protein absorption.
Dietary protein absorption in neonatal mammals and fishes relies on the function of a specialized and conserved population of highly absorptive lysosome-rich enterocytes (LREs). The gut microbiome has been shown to enhance absorption of nutrients, such as lipids, by intestinal epithelial cells. However, whether protein absorption is also affected by the gut microbiome is poorly understood. Here, we investigate connections between protein absorption and microbes in the zebrafish gut. Using live microscopy-based quantitative assays, we find that microbes slow the pace of protein uptake and degradation in LREs. While microbes do not affect the number of absorbing LRE cells, microbes lower the expression of endocytic and protein digestion machinery in LREs. Using transgene-assisted cell isolation and single cell RNA-sequencing, we characterize all intestinal cells that take up dietary protein. We find that microbes affect expression of bacteria-sensing and metabolic pathways in LREs, and that some secretory cell types also take up protein and share components of protein uptake and digestion machinery with LREs. Using custom-formulated diets, we investigated the influence of diet and LRE activity on the gut microbiome. Impaired protein uptake activity in LREs, along with a protein-deficient diet, alters the microbial community and leads to an increased abundance of bacterial genera that have the capacity to reduce protein uptake in LREs. Together, these results reveal that diet-dependent reciprocal interactions between LREs and the gut microbiome regulate protein absorption.
Antimicrobial peptides (AMPs) are attractive candidates to combat antibiotic resistance for their capability to target biomembranes and restrict a wide range of pathogens. It is a daunting challenge to discover novel AMPs due to their sparse distributions in a vast peptide universe, especially for peptides that demonstrate potencies for both bacterial membranes and viral envelopes. Here, we establish a de novo AMP design framework by bridging a deep generative module and a graph-encoding activity regressor. The generative module learns hidden ‘grammars’ of AMP features and produces candidates sequentially pass antimicrobial predictor and antiviral classifiers. We discovered 16 bifunctional AMPs and experimentally validated their abilities to inhibit a spectrum of pathogens in vitro and in animal models. Notably, P076 is a highly potent bactericide with the minimal inhibitory concentration of 0.21 μM against multidrug-resistantAcinetobacter baumannii, while P002 broadly inhibits five enveloped viruses. Our study provides feasible means to uncover the sequences that simultaneously encode antimicrobial and antiviral activities, thus bolstering the function spectra of AMPs to combat a wide range of drug-resistant infections.
Mycobacterium tuberculosis(Mtb) infection of macrophages reprograms cellular metabolism to promote lipid retention. While it is clearly known that intracellularMtbutilize host-derived lipids to maintain infection, the role of macrophage lipid processing on the bacteria’s ability to access the intracellular lipid pool remains undefined. We utilized a CRISPR-Cas9 genetic approach to assess the impact of sequential steps in fatty acid metabolism on the growth of intracellularMtb. Our analyses demonstrate that macrophages that cannot either import, store, or catabolize fatty acids restrictMtbgrowth by both common and divergent antimicrobial mechanisms, including increased glycolysis, increased oxidative stress, production of pro-inflammatory cytokines, enhanced autophagy, and nutrient limitation. We also show that impaired macrophage lipid droplet biogenesis is restrictive toMtbreplication, but increased induction of the same fails to rescueMtbgrowth. Our work expands our understanding of how host fatty acid homeostasis impactsMtbgrowth in the macrophage.
Investigating how the production of insulin is regulated in fruit flies reveals surprising insights that may help to better understand how this process unfolds in humans.
Antimicrobial peptides (AMPs) are attractive candidates to combat antibiotic resistance for their capability to target biomembranes and restrict a wide range of pathogens. It is a daunting challenge to discover novel AMPs due to their sparse distributions in a vast peptide universe, especially for peptides that demonstrate potencies for both bacterial membranes and viral envelopes. Here, we establish a de novo AMP design framework by bridging a deep generative module and a graph-encoding activity regressor. The generative module learns hidden ‘grammars’ of AMP features and produces candidates sequentially pass antimicrobial predictor and antiviral classifiers. We discovered 16 bifunctional AMPs and experimentally validated their abilities to inhibit a spectrum of pathogens in vitro and in animal models. Notably, P076 is a highly potent bactericide with the minimal inhibitory concentration of 0.21 μM against multidrug-resistantAcinetobacter baumannii, while P002 broadly inhibits five enveloped viruses. Our study provides feasible means to uncover the sequences that simultaneously encode antimicrobial and antiviral activities, thus bolstering the function spectra of AMPs to combat a wide range of drug-resistant infections.
RNA interference (RNAi) is a conserved pathway that utilizes Argonaute proteins and their associated small RNAs to exert gene regulatory function on complementary transcripts. While the majority of germline-expressed RNAi proteins reside in perinuclear germ granules, it is unknown whether and how RNAi pathways are spatially organized in other cell types. Here, we find that the small RNA biogenesis machinery is spatially and temporally organized duringCaenorhabditis elegansembryogenesis. Specifically, the RNAi factor, SIMR-1, forms visible concentrates during mid-embryogenesis that contain an RNA-dependent RNA polymerase, a poly-UG polymerase, and the unloaded nuclear Argonaute protein, NRDE-3. Curiously, coincident with the appearance of the SIMR granules, the small RNAs bound to NRDE-3 switch from predominantly CSR-class 22G-RNAs to ERGO-dependent 22G-RNAs. NRDE-3 binds ERGO-dependent 22G-RNAs in the somatic cells of larvae and adults to silence ERGO-target genes; here we further demonstrate that NRDE-3-bound, CSR-class 22G-RNAs repress transcription in oocytes. Thus, our study defines two separable roles for NRDE-3, targeting germline-expressed genes during oogenesis to promote global transcriptional repression, and switching during embryogenesis to repress recently duplicated genes and retrotransposons in somatic cells, highlighting the plasticity of Argonaute proteins and the need for more precise temporal characterization of Argonaute-small RNA interactions.
Haploinsufficiency forGATA6is associated with congenital heart disease (CHD) with variable comorbidity of pancreatic or diaphragm defects, although the etiology of disease is not well understood. Here, we used cardiac directed differentiation from human embryonic stem cells (hESCs) as a platform to study GATA6 function during early cardiogenesis. GATA6 loss-of-function hESCs had a profound impairment in cardiac progenitor cell (CPC) specification and cardiomyocyte (CM) generation due to early defects during the mesendoderm and lateral mesoderm patterning stages. Profiling by RNA-seq and CUT&RUN identified genes of the WNT and BMP programs regulated by GATA6 during early mesoderm patterning. Furthermore, interactome analysis detected GATA6 binding with developmental transcription factors and chromatin remodelers, suggesting cooperative regulation of cardiac lineage gene accessibility. We show that modulating WNT and BMP inputs during the first 48 hr of cardiac differentiation is sufficient to partially rescue CPC and CM defects inGATA6heterozygous and homozygous mutant hESCs. This study provides evidence of the regulatory functions for GATA6 directing human precardiac mesoderm patterning during the earliest stages of cardiogenesis to further our understanding of haploinsufficiency causing CHD and the co-occurrence of cardiac and other organ defects caused by humanGATA6mutations.
Virion Infectivity Factor (Vif) of the Human Immunodeficiency Virus type 1 (HIV-1) targets and degrades cellular APOBEC3 proteins, key regulators of intrinsic and innate antiretroviral immune responses, thereby facilitating HIV-1 infection. While Vif’s role in degrading APOBEC3G is well-studied, Vif is also known to cause cell cycle arrest, but the detailed nature of Vif’s effects on the cell cycle has yet to be delineated. In this study, we employed high-temporal resolution single-cell live imaging and super-resolution microscopy to monitor individual cells during Vif-induced cell cycle arrest. Our findings reveal that Vif does not affect the G2/M boundary as previously thought. Instead, Vif triggers a unique and robust pseudo-metaphase arrest, distinct from the mild prometaphase arrest induced by Vpr. During this arrest, chromosomes align properly and form the metaphase plate, but later lose alignment, resulting in polar chromosomes. Notably, Vif, unlike Vpr, significantly reduces the levels of both Protein Phosphatase 1 (PP1) and 2 A (PP2A) at kinetochores, which regulate chromosome-microtubule interactions. These results unveil a novel role for Vif in kinetochore regulation that governs the spatial organization of chromosomes during mitosis.
Haploinsufficiency forGATA6is associated with congenital heart disease (CHD) with variable comorbidity of pancreatic or diaphragm defects, although the etiology of disease is not well understood. Here, we used cardiac directed differentiation from human embryonic stem cells (hESCs) as a platform to study GATA6 function during early cardiogenesis. GATA6 loss-of-function hESCs had a profound impairment in cardiac progenitor cell (CPC) specification and cardiomyocyte (CM) generation due to early defects during the mesendoderm and lateral mesoderm patterning stages. Profiling by RNA-seq and CUT&RUN identified genes of the WNT and BMP programs regulated by GATA6 during early mesoderm patterning. Furthermore, interactome analysis detected GATA6 binding with developmental transcription factors and chromatin remodelers, suggesting cooperative regulation of cardiac lineage gene accessibility. We show that modulating WNT and BMP inputs during the first 48 hr of cardiac differentiation is sufficient to partially rescue CPC and CM defects inGATA6heterozygous and homozygous mutant hESCs. This study provides evidence of the regulatory functions for GATA6 directing human precardiac mesoderm patterning during the earliest stages of cardiogenesis to further our understanding of haploinsufficiency causing CHD and the co-occurrence of cardiac and other organ defects caused by humanGATA6mutations.
Fiber photometry has become a popular technique to measure neural activity in vivo, but common analysis strategies can reduce the detection of effects because they condensewithin-trialsignals into summary measures, and discard trial-level information by averagingacross-trials. We propose a novel photometry statistical framework based on functional linear mixed modeling, which enables hypothesis testing of variable effects atevery trial time-point, and uses trial-level signals without averaging. This makes it possible to compare the timing and magnitude of signals across conditions while accounting for between-animal differences. Our framework produces a series of plots that illustrate covariate effect estimates and statistical significance at each trial time-point. By exploiting signal autocorrelation, our methodology yieldsjoint95% confidence intervals that account for inspecting effects across the entire trial and improve the detection of event-related signal changes over common multiple comparisons correction strategies. We reanalyze data from a recent study proposing a theory for the role of mesolimbic dopamine in reward learning, and show the capability of our framework to reveal significant effects obscured by standard analysis approaches. For example, our method identifies two dopamine components with distinct temporal dynamics in response to reward delivery. In simulation experiments, our methodology yields improved statistical power over common analysis approaches. Finally, we provide an open-source package and analysis guide for applying our framework.
Longitudinal neuroimaging studies offer valuable insight into brain development, ageing, and disease progression over time. However, prevailing analytical approaches rooted in our understanding of population variation are primarily tailored for cross-sectional studies. To fully leverage the potential of longitudinal neuroimaging, we need methodologies that account for the complex interplay between population variation and individual dynamics. We extend the normative modelling framework, which evaluates an individual’s position relative to population standards, to assess an individual’s longitudinalchangecompared to the population’s standard dynamics. Using normative models pre-trained on over 58,000 individuals, we introduce a quantitative metric termed ‘z-diff’ score, which quantifies a temporal change in individuals compared to a population standard. This approach offers advantages in flexibility in dataset size and ease of implementation. We applied this framework to a longitudinal dataset of 98 patients with early-stage schizophrenia who underwent MRI examinations shortly after diagnosis and 1 year later. Compared to cross-sectional analyses, showing global thinning of grey matter at the first visit, our method revealed a significant normalisation of grey matter thickness in the frontal lobe over time—an effect undetected by traditional longitudinal methods. Overall, our framework presents a flexible and effective methodology for analysing longitudinal neuroimaging data, providing insights into the progression of a disease that would otherwise be missed when using more traditional approaches.
Human autonomic neuronal cell models are emerging as tools for modelling diseases such as cardiac arrhythmias. In this systematic review, we compared thirty-three articles applying fourteen different protocols to generate sympathetic neurons and three different procedures to produce parasympathetic neurons. All methods involved the differentiation of human pluripotent stem cells, and none employed permanent or reversible cell immortalization. Almost all protocols were reproduced in multiple pluripotent stem cell lines, and over half show evidence of neural firing capacity. Common limitations in the field are a lack of three-dimensional models and models including multiple cell types. Sympathetic neuron differentiation protocols largely mirrored embryonic development, with the notable absence of migration, axon extension, and target-specificity cues. Parasympathetic neuron differentiation protocols may be improved by including several embryonic cues promoting cell survival, cell maturation, or ion channel expression. Moreover, additional markers to define parasympathetic neuronsin vitromay support the validity of these protocols. Nonetheless, four sympathetic neuron differentiation protocols and one parasympathetic neuron differentiation protocol reported more than two thirds of cells expressing autonomic neuron markers. Altogether, these protocols promise to open new research avenues of human autonomic neuron development and disease modelling.
Research on brain plasticity, particularly in the context of deafness, consistently emphasizes the reorganization of the auditory cortex. But to what extent do all individuals with deafness show the same level of reorganization? To address this question, we examined the individual differences in functional connectivity (FC) from the deprived auditory cortex. Our findings demonstrate remarkable differentiation between individuals deriving from the absence of shared auditory experiences, resulting in heightened FC variability among deaf individuals, compared to more consistent FC in the hearing group. Notably, connectivity to language regions becomes more diverse across individuals with deafness. This does not stem from delayed language acquisition; it is found in deaf native signers, who are exposed to natural language since birth. However, comparing FC diversity between deaf native signers and deaf delayed signers, who were deprived of language in early development, we show that language experience also impacts individual differences, although to a more moderate extent. Overall, our research points out the intricate interplay between brain plasticity and individual differences, shedding light on the diverse ways reorganization manifests among individuals. It joins findings of increased connectivity diversity in blindness and highlights the importance of considering individual differences in personalized rehabilitation for sensory loss.
Evolution of gene expression frequently drives antibiotic resistance in bacteria. We had previously (Patel and Matange,eLife, 2021) shown that, inEscherichia coli, mutations at themgrBlocus were beneficial under trimethoprim exposure and led to overexpression of dihydrofolate reductase (DHFR), encoded by thefolAgene. Here, we show that DHFR levels are further enhanced by spontaneous duplication of a genomic segment encompassingfolAand spanning hundreds of kilobases. This duplication was rare in wild-typeE. coli. However, its frequency was elevated in alon-knockout strain, altering the mutational landscape early during trimethoprim adaptation. We then exploit this system to investigate the relationship between trimethoprim pressure andfolAcopy number. During long-term evolution,folAduplications were frequently reversed. Reversal was slower under antibiotic pressure, first requiring the acquisition of point mutations in DHFR or its promoter. Unexpectedly, despite resistance-conferring point mutations, some populations under high trimethoprim pressure maintainedfolAduplication to compensate for low abundance DHFR mutants. We find that evolution of gene dosage depends on expression demand, which is generated by antibiotic and exacerbated by proteolysis of drug-resistant mutants of DHFR. We propose a novel role for proteostasis as a determinant of copy number evolution in antibiotic-resistant bacteria.
Evolution of gene expression frequently drives antibiotic resistance in bacteria. We had previously (Patel and Matange,eLife, 2021) shown that, inEscherichia coli, mutations at themgrBlocus were beneficial under trimethoprim exposure and led to overexpression of dihydrofolate reductase (DHFR), encoded by thefolAgene. Here, we show that DHFR levels are further enhanced by spontaneous duplication of a genomic segment encompassingfolAand spanning hundreds of kilobases. This duplication was rare in wild-typeE. coli. However, its frequency was elevated in alon-knockout strain, altering the mutational landscape early during trimethoprim adaptation. We then exploit this system to investigate the relationship between trimethoprim pressure andfolAcopy number. During long-term evolution,folAduplications were frequently reversed. Reversal was slower under antibiotic pressure, first requiring the acquisition of point mutations in DHFR or its promoter. Unexpectedly, despite resistance-conferring point mutations, some populations under high trimethoprim pressure maintainedfolAduplication to compensate for low abundance DHFR mutants. We find that evolution of gene dosage depends on expression demand, which is generated by antibiotic and exacerbated by proteolysis of drug-resistant mutants of DHFR. We propose a novel role for proteostasis as a determinant of copy number evolution in antibiotic-resistant bacteria.
Expression quantitative trait loci (eQTLs) provide a key bridge between noncoding DNA sequence variants and organismal traits. The effects of eQTLs can differ among tissues, cell types, and cellular states, but these differences are obscured by gene expression measurements in bulk populations. We developed a one-pot approach to map eQTLs inSaccharomyces cerevisiaeby single-cell RNA sequencing (scRNA-seq) and applied it to over 100,000 single cells from three crosses. We used scRNA-seq data to genotype each cell, measure gene expression, and classify the cells by cell-cycle stage. We mapped thousands of local and distant eQTLs and identified interactions between eQTL effects and cell-cycle stages. We took advantage of single-cell expression information to identify hundreds of genes with allele-specific effects on expression noise. We used cell-cycle stage classification to map 20 loci that influence cell-cycle progression. One of these loci influenced the expression of genes involved in the mating response. We showed that the effects of this locus arise from a common variant (W82R) in the geneGPA1, which encodes a signaling protein that negatively regulates the mating pathway. The 82R allele increases mating efficiency at the cost of slower cell-cycle progression and is associated with a higher rate of outcrossing in nature. Our results provide a more granular picture of the effects of genetic variants on gene expression and downstream traits.
Longitudinal neuroimaging studies offer valuable insight into brain development, ageing, and disease progression over time. However, prevailing analytical approaches rooted in our understanding of population variation are primarily tailored for cross-sectional studies. To fully leverage the potential of longitudinal neuroimaging, we need methodologies that account for the complex interplay between population variation and individual dynamics. We extend the normative modelling framework, which evaluates an individual’s position relative to population standards, to assess an individual’s longitudinalchangecompared to the population’s standard dynamics. Using normative models pre-trained on over 58,000 individuals, we introduce a quantitative metric termed ‘z-diff’ score, which quantifies a temporal change in individuals compared to a population standard. This approach offers advantages in flexibility in dataset size and ease of implementation. We applied this framework to a longitudinal dataset of 98 patients with early-stage schizophrenia who underwent MRI examinations shortly after diagnosis and 1 year later. Compared to cross-sectional analyses, showing global thinning of grey matter at the first visit, our method revealed a significant normalisation of grey matter thickness in the frontal lobe over time—an effect undetected by traditional longitudinal methods. Overall, our framework presents a flexible and effective methodology for analysing longitudinal neuroimaging data, providing insights into the progression of a disease that would otherwise be missed when using more traditional approaches.
Fiber photometry has become a popular technique to measure neural activity in vivo, but common analysis strategies can reduce the detection of effects because they condensewithin-trialsignals into summary measures, and discard trial-level information by averagingacross-trials. We propose a novel photometry statistical framework based on functional linear mixed modeling, which enables hypothesis testing of variable effects atevery trial time-point, and uses trial-level signals without averaging. This makes it possible to compare the timing and magnitude of signals across conditions while accounting for between-animal differences. Our framework produces a series of plots that illustrate covariate effect estimates and statistical significance at each trial time-point. By exploiting signal autocorrelation, our methodology yieldsjoint95% confidence intervals that account for inspecting effects across the entire trial and improve the detection of event-related signal changes over common multiple comparisons correction strategies. We reanalyze data from a recent study proposing a theory for the role of mesolimbic dopamine in reward learning, and show the capability of our framework to reveal significant effects obscured by standard analysis approaches. For example, our method identifies two dopamine components with distinct temporal dynamics in response to reward delivery. In simulation experiments, our methodology yields improved statistical power over common analysis approaches. Finally, we provide an open-source package and analysis guide for applying our framework.
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AbstractAcute intoxication from Δ9-tetrahydrocannabinol (THC, the primary active ingredient of cannabis) can lead to neurocognitive impairment and interference with day-to-day operations, such as driving. Present evaluations of THC-induced impairment in legal settings rely on biological drug tests that solely establish cannabis use, rather than cannabis impairment. The current study evaluated the metabolome in blood collected from occasional and chronic cannabis users (N= 35) at baseline and following treatments with cannabis (300 μg/kg THC) and placebo, with the aim to identify unique metabolic alterations that are associated with acute cannabis intoxication and cannabis use frequency. Blood samples were collected at baseline and repeatedly during 70 min after treatment. Sustained attention performance and ratings of subjective high were taken twice within 40 min after treatment. Metabolomic fingerprints of occasional and chronic cannabis users were distinctly different at baseline, when both groups were not intoxicated. A total of 14 metabolites, mainly related to endocannabinoid and amino acid metabolism, were identified that distinguished chronic from occasional cannabis users and that yielded a discriminant analysis model with an 80% classification rate (95% CI: 61–91%). Distinct metabolomic fingerprints were found for occasional cannabis users who, in contrast to chronic cannabis users, showed attentional impairment and elevated ratings of subjective high during cannabis intoxication. These included increments in organic acids, β-hydroxybutyrate and second messenger ceramides. The current study demonstrates the feasibility of the metabolomics approach to identify metabolic changes that are specific to the neurocognitive state of cannabis intoxication and to the history of cannabis use.
AbstractNeuroimaging research has yet to elucidate whether reported gray matter volume (GMV) alterations in major depressive disorder (MDD) exist already before the onset of the first episode. Recruitment of presently healthy individuals with a subsequent transition to MDD (converters) is extremely challenging but crucial to gain insights into neurobiological vulnerability. Hence, we compared converters to patients with MDD and sustained healthy controls (HC) to distinguish pre-existing neurobiological markers from those emerging later in the course of depression. Combining two clinical cohorts (n= 1709), voxel-based morphometry was utilized to analyze GMV ofn= 45 converters,n= 748 patients with MDD, andn= 916 HC in a region-of-interest approach and exploratory whole-brain. By contrasting the subgroups and considering both remission state and reported recurrence at a 2-year clinical follow-up, we stepwise disentangled effects of (1) vulnerability, (2) the acute depressive state, and (3) an initial vs. a recurrent episode. Analyses revealed higher amygdala GMV in converters relative to HC (ptfce-FWE= 0.037,d= 0.447) and patients (ptfce-FWE= 0.005,d= 0.508), remaining significant when compared to remitted patients with imminent recurrence. Lower GMV in the dorsolateral prefrontal cortex (ptfce-FWE< 0.001,d= 0.188) and insula (ptfce-FWE= 0.010,d= 0.186) emerged in patients relative to HC but not to converters, driven by patients with acute MDD. By examining one of the largest available converter samples in psychiatric neuroimaging, this study allowed a first determination of neural markers for an impending initial depressive episode. Our findings suggest a temporary vulnerability, which in combination with other common risk factors might facilitate prediction and in turn improve prevention of depression.
AbstractAccumulating evidence indicates that drug addiction may lead to adaptive behavioral changes in offspring, potentially due to epigenetic modifications in parental germline. However, the underlying mechanisms remain inadequately understood. In this study, we show that paternal heroin self-administration (SA) increased heroin-seeking behavior in the F1 generation, when compared with offspring sired by yoke-infused control males, indicating cross-generational impact of paternal voluntary heroin seeking behavior. Notably, the increase of heroin seeking behavior in offspring was replicated by zygotic microinjection of sperm RNAs derived from sperm of heroin-SA-experienced rats. Analysis of non-coding RNAs in spermatozoa revealed coordinated changes in miRNA content between the nucleus accumbens and spermatozoa. We validated that restoration of miR-19b downregulation in sperm RNA from self-administration-experienced rats, in parallel with its overexpression in the nucleus accumbens of F1 offspring sired by heroin-SA-experienced fathers, reversed the increased heroin SA observed in these F1 offspring. Taken together, our findings suggest in rats that paternal heroin self-administration induces epigenetic changes in both brain and sperm miRNA, with miR-19b downregulation playing a critical role in mediating the epigenetic inheritance of increased heroin self-administration behavior in the F1 generation.
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AbstractThe drug development process in psychiatry faces significant challenges due to low reproducibility rates in animal testing, which often leads to translation failures. To address this issue, we introduce a new approach in psychiatric drug development: a preclinical randomized controlled trial (preRCT). To demonstrate its potential utility, we conducted a multi-center preRCT using the alcohol deprivation effect (ADE) model to assess the impact of ketamine and R-ketamine on alcohol relapse across three European research centers. Ketamine (20 mg/kg) significantly reduced relapse, while R-ketamine showed efficacy only in females. A higher dose of R-ketamine (40 mg/kg) was also effective in males. These sex-dependent effects were linked to plasma R-ketamine levels, which were two-fold higher in female compared to male rats. Notably, R-ketamine demonstrated a lasting reduction in alcohol consumption without adverse effects. In conclusion, our preRCT demonstrates R-ketamine’s effectiveness in reducing alcohol relapse and supports translation to a clinical RCT that accounts for sex-dependent effects.
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AbstractBipolar disorder (BD) is a severe psychiatric disorder characterized by alternating manic and depressive episodes. The molecular mechanisms underlying the transition between mania and depression remain unclear. Utilizing a mania animal model induced by ouabain, we observed reduced phosphorylated level of cyclic AMP-responsive element-binding protein (pCREB) and Period (PER)2 expression in the cornu ammonis (CA1) region of the hippocampus, which were restored by lithium treatment. shRNA knockdown of CREB or Per2 in CA1 region induced mania-like behavior, while overexpression of both factors resulted in depression-like behavior. Furthermore, our protein analyses revealed that the upregulation or downregulation of CREB or Per2 influenced each other’s expression. Co-immunoprecipitation results demonstrated that CREB interacts with PER2. Taken together, our data suggest for potential inter-regulatory crosstalk between CREB–PER2 in hippocampal CA1 region, which mediates the transition between mania- and depression-like behaviors.
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AbstractCognitive-behavioral therapy (CBT) is a primary treatment for depression. Although previous research has underscored the significant roles of white matter (WM) alterations and maladaptive parenting in depression risk, their associations with CBT response remain largely unknown. This longitudinal study investigated the interplay of WM integrity changes over time, treatment response, and parenting style in patients with depression. Diffusion-tensor-imaging and clinical data were assessed inn= 65 (55% female) patients with depression before and after 20 CBT sessions andn= 65 (68% female) healthy controls (HC) in a naturalistic design. Linear-mixed-effect models compared changes in fractional anisotropy (FA) between groups and tested associations between FA changes and symptom changes. It was investigated whether parenting style predicts depressive symptoms at follow-up and whether FA changes mediate this association. Patients showed differential FA changes over time in the corpus callosum and corona radiata compared to HC (ptfce-FWE= 0.008). Increases in FA in the corpus callosum, corona radiata and superior longitudinal fasciculus were linked to symptom improvement after CBT in patients (ptfce-FWE= 0.023). High parental care (pFDR= 0.010) and low maternal overprotection (pFDR= 0.001) predicted fewer depressive symptoms at follow-up. The association between maternal overprotection and depressive symptoms at follow-up was mediated by FA changes (pFDR= 0.044). Robustness checks—controlling for outliers, non-linear age effects, clinical characteristics, and patient subgroups—supported these results. Overall, patients with depression show changes in WM integrity following CBT, which are linked to treatment response. The results highlight the significance of early life adversities and related microstructural changes in the effectiveness of CBT for treating depression.
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AbstractCraving in alcohol drinkers is often triggered by chemosensory cues, such as taste and smell, which are linked to brain network connectivity. This study aimed to investigate whether these brain connectivity patterns could predict alcohol intake in young adults. Resting-state fMRI data were obtained from the Human Connectome Project (HCP) Young Adult cohort, comprising 1003 participants. Functional connectomes generated from 100 independent components were analyzed, identifying significant connections correlated with taste and odor scores after applying a false discovery rate (FDR) correction using the Benjamini-Hochberg (BH) method. These significant connections were then utilized as predictors in general linear models for various alcohol intake metrics. The models were validated in an independent sample to assess their accuracy. The training sample (n= 702) and the validation sample (n= 117) showed no significant demographic differences. Out of 742 possible connections, 41 related to odor and 25 related to taste passed the significance threshold (P< 0.05) after FDR-BH correction. Notable predictors included visual-visual connectivity (node32-node13: β = 0.028,P= 0.02) for wine consumption and connectivity between the ventral attention network (VAN) and the frontal parietal/caudate nucleus (FP/CN) (node27-node9: β = −0.31,P= 0.04) for total alcohol intake in the past-week and maximum number of drinks per day in the past-year. The predictive models demonstrated strong accuracy, with root mean square error (RMSE) values of 5.15 for odor-related models and 5.14 for taste-related models. The F1 scores were 0.74 for the odor model and 0.71 for the taste model, indicating reliable performance. These findings suggest that specific patterns of brain connectivity associated with taste and olfactory perception may serve as predictors of alcohol consumption behaviors in young adults. Our study highlight the need for longitudinal research to evaluate the potential of taste- and smell-related brain connectivity patterns for early screening and targeted interventions, as well as their role in personalized treatment strategies for individuals at risk of AUD.
AbstractAbnormalities during rapid eye movement (REM) sleep contribute to the pathophysiology of major depressive disorder (MDD), but few studies have explored the relationship between REM sleep and treatment-resistant depression (TRD). In MDD, REM sleep abnormalities often manifest as alterations in total night REM Density (RD), RD in the first REM period (RD1), and REM Latency (RL). Among these, RD1 is notably considered a potential endophenotype of depression. This study compared REM sleep markers between 63 drug-free individuals with TRD (39 F/24 M) and 41 healthy volunteers (25 F/16 M). It also investigated the effects of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, on these REM sleep variables. Specifically, the study investigated whether RD1 could predict antidepressant response to ketamine. TRD participants showed higher RD1 and shorter RL at baseline compared to HVs, as assessed via non-parametric tests, but Total Night RD did not differ between the two groups. Ketamine treatment decreased RD1 in TRD participants but did not affect Total Night RD or RL. As assessed via the Support Vector Machine (SVM) algorithm, baseline RD1 level moderately predicted antidepressant response to ketamine versus non-response (area under the receiver operating characteristic (ROC) curve (AUC) = 0.73, with a median accuracy of 0.75), wherein TRD participants with higher baseline RD1 were more likely to respond to ketamine. These results underscore the utility of RD1 for identifying individuals most likely to benefit from ketamine treatment, enabling more targeted and effective therapeutic strategies. Clinical Trials Identifier: NCT00088699, NCT01204918.
AbstractADHD is a chronic neurodevelopmental disorder that significantly affects life outcomes, and current treatments often have adverse side effects, high abuse potential, and a 25% non-response rate, highlighting the need for new therapeutics. This study investigates amlodipine, an L-type calcium channel blocker, as a potential foundation for developing a novel ADHD treatment by integrating findings from animal models and human genetic data. Amlodipine reduced hyperactivity in SHR rats and decreased both hyperactivity and impulsivity inadgrl3.1−/− zebrafish. It also crosses the blood-brain barrier, reducing telencephalic activation. Crucially, Mendelian Randomization analysis linked ADHD to genetic variations in L-type calcium channel subunits (α1-C; CACNA1C, β1; CACNB1, α2δ3; CACNA2D3) targeted by amlodipine, while polygenic risk score analysis showed symptom mitigation in individuals with high ADHD genetic liability. With its well-tolerated profile and efficacy across species, supported by genetic evidence, amlodipine shows potential to be refined and developed into a novel treatment for ADHD.
AbstractDeficits in behavioral or cognitive flexibility that are linked to altered activity in both cortical and subcortical brain regions, are often observed across multiple neuropsychiatric disorders. The medial prefrontal cortex (mPFC)-nucleus accumbens (NAc) pathway in rats plays a critical role in flexible control of behavior. However, the modulation of this pathway on activity and functional connectivity with the rest of the brain remains unclear. In this study, we first confirmed the role of the mPFC-NAc pathway in behavioral flexibility using a set-shifting task in rats and then evaluated the causal effects of mPFC-NAc activation induced by chemogenetic stimulation of the terminal axons of the NAc with DREADD expression on whole-brain activity and functional connectivity measured by functional MRI. mPFC-NAc activation improved performance on the set-shifting task by reducing perseverative errors. Additionally, stimulation of this pathway increased activity in a set of brain regions within the basal ganglia-thalamus-cortical loop network including NAc, thalamus, hypothalamus and various connected cortical regions, while also decreased functional connectivity strength of NAc-mPFC, NAc-secondary motor cortex (M2), and various cortical circuits. Moreover, performance on the set-shifting task was related to the functional connectivity strength of the above frontostriatal and cortical circuits. These findings provide insights into the link between specific frontostriatal circuits on decision making flexibility, which may inform potential future interventions for behavioral flexibility deficits.
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AbstractMethamphetamine (MA) is a potent psychostimulant capable of exerting both rewarding and aversive effects, the balance of which likely drives variation in voluntary MA intake. Understanding the genetic factors underlying sensitivity to these effects of MA is critical for developing effective treatments. The activity of dorsal raphe serotonin neurons is linked to reward processing. Here, we performed whole-cell patch-clamp electrophysiology in dorsal raphe serotonin neurons from mice with high or low MA intake corresponding with high or low MA reward sensitivity. The MA drinking (MADR) mice consist of the MA reward sensitive MA high drinking (MAHDR) and the MA reward insensitive MA low drinking (MALDR) lines. MA is a trace amine-associated receptor 1 (TAAR1) agonist, and MAHDR mice are homozygous for a mutation in theTaar1gene, Taar1m1J, that encodes non-functional TAAR1, whereas MALDR mice possess at least one copy of the referenceTaar1+allele that encodes functional TAAR1. Our previous research using CRISPR-Cas9-generated MAHDR-Taar1+/+knock-in mice in whichTaar1m1Jwas replaced withTaar1+, and non-edited MAHDR-Taar1m1J/m1Jcontrols demonstrated that lack of TAAR1 function is critical for heightened MA consumption and MA reward sensitivity. Here, electrophysiological recordings in the MADR lines demonstrate a MA-induced decrease in dorsal raphe serotonin neuron activity from MALDR, but not MAHDR mice. However, in the presence of serotonin autoreceptor antagonists, MA potentiates dorsal raphe serotonin neuron activity of MAHDR, but not MALDR mice. Importantly, potentiation in the presence of the antagonists is abolished in knock-in mice expressing functional TAAR1. The knock-in mice did not display binge-level MA intake, consistent with the loss of MA-reward sensitivity previously reported in mice with functional TAAR1. Finally, because MA is a substrate of the serotonin transporter, we evaluated whether the serotonin transporter is necessary for MA-induced potentiation of dorsal raphe serotonin neuron activity in mice with non-functional TAAR1. The serotonin transporter antagonist fluoxetine blocks MA-induced potentiation for both MAHDR and MAHDR-Taar1m1J/m1Jmice. Thus, TAAR1 function directly impacts MA reward sensitivity and MA intake and serves as a critical regulator of MA-induced activity of dorsal raphe serotonin neurons through its interaction with the serotonin transporter.
AbstractThe atypical antipsychotic clozapine targets multiple receptor systems beyond the dopaminergic pathway and influences prepulse inhibition (PPI), a critical translational measure of sensorimotor gating. Since PPI is modulated by atypical antipsychotics such as risperidone and clozapine, we hypothesized that p11—an adaptor protein associated with anxiety- and depressive-like behaviors and G-protein-coupled receptor function—might modulate these effects. In this study, we assessed the role of p11 in clozapine’s PPI-enhancing effect by testing wild-type and global p11 knockout (KO) mice in response to haloperidol, risperidone, and clozapine. We also performed structural and functional brain imaging. Contrary to our expectation that anxiety-like p11-KO mice would exhibit an augmented startle response and heightened sensitivity to clozapine, PPI tests showed that p11-KO mice were unresponsive to the PPI-enhancing effects of risperidone and clozapine. Imaging revealed distinct regional brain volume differences and reduced hippocampal connectivity in p11-KO mice, with significantly blunted clozapine-induced connectivity changes in the CA1 region. Our findings highlight a novel role for p11 in modulating clozapine’s effects on sensorimotor gating and hippocampal connectivity, offering new insight into its functional pathways.
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AbstractCannabis use disorder is particularly prevalent and impairing among young people, and evidence-based treatments are limited. Prior trials of N-acetylcysteine, added to contingency management as a platform behavioral intervention, yielded positive findings in youth but not in adults. This trial sought to rigorously evaluate whether N-acetylcysteine is efficacious in youth when not paired with a robust behavioral treatment platform. Treatment-seeking youth with cannabis use disorder (N= 192, ages 14–21) were randomized to receive a double-blind 12-week course of oral N-acetylcysteine 1200 mg or placebo twice daily; all received weekly medical management and brief behavioral counseling. The primary efficacy outcome was the proportion of negative urine cannabinoid tests during treatment, compared between groups. An array of self-report and urine testing measures were examined secondarily to assess cannabis use reduction and cessation outcomes. The N-acetylcysteine and placebo groups did not differ in proportion of negative urine cannabinoid tests (RR = 0.93, 95% CI = 0.53, 1.64;p= 0.80) or self-reported cannabis abstinence (RR = 1.02, 95% CI = 0.63, 1.65;p= 0.93) during treatment. The mean percentage of cannabis use days and grams of cannabis used per using day decreased over time during treatment but did not differ between groups. More N-acetylcysteine than placebo treated participants reported gastrointestinal adverse events (63/98 versus 37/94, χ21= 11.9p< 0.001); adverse events were otherwise similar between groups. Findings indicate that N-acetylcysteine is not efficacious for youth cannabis use disorder when not paired with contingency management, highlighting the potentially crucial role of a robust behavioral treatment platform in facilitating prior positive efficacy findings with N-acetylcysteine.Trial Registration: Clinicaltrials.gov identifier NCT03055377
AbstractAnimal studies have reported associations of early maternal separation with altered μ-opioid receptor function but data on humans are scarce. We now investigated whether childhood family environment is related to μ-opioid receptor availability in the human brain in adulthood. Healthy participants (n= 37–39 in the analyses) were recruited from the prospective population-based Young Finns Study (YFS) that started in 1980. Childhood family environment was evaluated in 1980, including scores for stress-prone life events, disadvantageous emotional family atmosphere, and adverse socioeconomic environment. We used positron emission tomography (PET) with radioligand [11C]carfentanil to measure μ–opioid receptor availability in adulthood. Age- and sex-adjusted analyses showed that exposure to stress-prone life events in childhood was related to lower μ-opioid receptor binding in the orbitofrontal cortex, hippocampus, putamen, amygdala, insula, thalamus, anterior cingulate cortex, and dorsal caudate in adulthood (when compared to participants not exposed to stress-prone life events). Unfavorable socioeconomic family environment or disadvantageous emotional family atmosphere was not associated with μ-opioid receptor availability in adulthood. In conclusion, exposure to environmental instability (i.e., to stress-prone life events below traumatic threshold) during early development is associated with dysregulation of the u-opioid receptor transmission in adulthood. The findings increase understanding of the neurobiological mechanisms involved in the associations between childhood adversities and adulthood mental disorders.
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AbstractSocial relationships are central to well-being. A subgroup of afferent nerve fibers, C-tactile (CT) afferents, are primed to respond to affective, socially relevant touch and may mitigate the effects of stress. The endocannabinoid ligand anandamide (AEA) modulates both social reward and stress. We thus hypothesized that AEA levels would be associated with the perceived pleasantness of affective touch in humans. Across two studies, we explored perceptions of affective, socially relevant touch and general affective stimuli. In study 1, adult participants (N = 101) were recruited based on presence (CM+) or absence (CM−) of documented childhood maltreatment (N = 52 CM+; N = 49 CM−). In study 2, healthy individuals were randomized to receive an inhibitor of fatty acid amide hydrolase (FAAH; PF-04457845) to increase AEA levels (n = 16) or placebo (n = 29). Outcomes included self-report ratings of touch pleasantness and intensity, valence and arousal ratings of affective images, and plasma levels of endocannabinoids AEA and 2-AG, cortisol, and oxytocin. In study 1, higher AEA levels were associated with a reduced preference for affective, CT-optimal touch. In study 2, pharmacological elevation of AEA resulted in reduced preference for affective touch. These effects were specific to social processing, as AEA levels were not related to ratings of affective images. In contrast to our hypothesis, elevated AEA was associated with reduced pleasantness ratings of CT-optimal, affective touch. This provides novel, in-human data linking AEA to social processing, adding nuance to the rationale for its use as a potential novel therapeutic target in disordered in social processing.
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The bright colors observed across the animal world are often used during mate choice. An exciting new study inPLOS Biologysuggests genetic and neural mechanisms contributing to the evolution of visual mating decisions inHeliconiusbutterflies.
Stem cells have the unique ability among adult cells to give rise to cells of different identities. To do so, they must change gene expression in response to environmental signals. Much work has focused on how transcription is regulated to achieve these changes; however, in many cell types, transcripts and proteins correlate poorly, indicating that post-transcriptional regulation is important. To assess how translational control can influence stem cell fate, we use theDrosophilatestis as a model. The testis niche secretes a ligand to activate the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in two stem cell populations, germline stem cells (GSCs) and somatic cyst stem cells (CySCs). We find that global translation rates are high in CySCs and decrease during differentiation, and that JAK/STAT signaling regulates translation. To determine how translation was regulated, we knocked down translation initiation factors and found that the cap binding complex, eIF4F, is dispensable in differentiating cells, but is specifically required in CySCs for self-renewal, acting downstream of JAK/STAT activity. Moreover, we identify eIF3d1 as a key regulator of CySC fate, and show that two eIF3d1 residues subject to regulation by phosphorylation are critical to maintain CySC self-renewal. We further show that Casein Kinase II (CkII), which controls eIF3d1 phosphorylation, influences the binding of eIF3d and eIF4F in mammalian cells, and that CkII expression is sufficient to restore CySC function in the absence of JAK/STAT. We propose a model in which niche signals regulate a specific translation programme in which only some mRNAs are translated. The mechanism we identify allows stem cells to switch between modes of translation, adding a layer of regulation on top of transcription and providing cells with the ability to rapidly change gene expression upon receiving external stimuli.
Histone modifications play a key role in regulating gene expression and cell fate during development and disease. Current methods for cell-type-specific genome-wide profiling of histone modifications require dissociation and isolation of cells and are not compatible with all tissue types. Here we adapt Targeted DamID (TaDa) to recognize specific histone marks, by fusing chromatin-binding proteins or single-chain antibodies to Dam, anEscherichia coliDNA adenine methylase. When combined with TaDa, this enables cell-type-specific chromatin profiling in intact tissues or organisms. We first profiled H3K4me3, H3K9ac, H3K27me3 and H4K20me1 in vivo in neural stem cells of the developingDrosophilabrain. Next, we mapped cell-type-specific H3K4me3, H3K9ac and H4K20me1 distributions in the developing mouse brain. Finally, we injected RNA encoding DamID constructs into 1-cell stageXenopusembryos to profile H3K4me3 distribution during gastrulation and neurulation. These results illustrate the versatility of TaDa to profile cell-type-specific histone marks throughout the genome in diverse model systems.
Many studies have linked genetic variation to behavior, but few connect to the intervening neural circuits that underlie the arc from sensation to action. Here, we used a combination of genome-wide association (GWA), developmental gene expression, and photoreceptor electrophysiology to investigate the architecture of mate choice behavior inHeliconius cydnobutterflies, a clade where males identify preferred mates based on wing color patterns. We first found that the GWA variants most strongly associated with male mate choice were tightly linked to the gene controlling wing color in theKlocus, consistent with previous mapping efforts. RNA-seq across developmental time points then showed that seven genes near the top GWA peaks were differentially expressed in the eyes, optic lobes, or central brain of white and yellowH. cydnomales, many of which have known functions in the development and maintenance of synaptic connections. In the visual system of these butterflies, we identified a striking physiological difference between yellow and white males that could provide an evolutionarily labile circuit motif in the eye to rapidly switch behavioral preference. Using single-cell electrophysiology recordings, we found that some ultraviolet (UV)-sensitive photoreceptors receive inhibition from long-wavelength photoreceptors in the male eye. Surprisingly, the proportion of inhibited UV photoreceptors was strongly correlated with male wing color, suggesting a difference in the early stages of visual processing that could plausibly influence courtship decisions. We discuss potential links between candidate genes and this physiological signature, and suggest future avenues for experimental work. Taken together, our results support the idea that alterations to the evolutionarily labile peripheral nervous system, driven by genetic and gene expression differences, can significantly and rapidly alter essential behaviors.
The prokaryote-specific ATP-binding cassette (ABC) peptide transporters are involved in various physiological processes and plays an important role in transporting naturally occurring antibiotics across the membrane to their intracellular targets. The dipeptide transporter DppABCDF in Gram-negative bacteria is composed of five distinct subunits, yet its assembly and underlying peptide import mechanism remain elusive. Here, we report the cryo-EM structures of the DppBCDF translocator fromEscherichia coliin both its apo form and in complexes bound to nonhydrolyzable or slowly hydrolyzable ATP analogs (AMPPNP and ATPγS), as well as the ATPγS-bound DppABCDF full transporter. Unlike the reported heterotrimericMycobacterium tuberculosisDppBCD translocator, theE. coliDppBCDF translocator is a heterotetramer, with a [4Fe-4S] cluster at the C-terminus of each ATPase subunit. Structural studies reveal that ATPγS/AMPPNP-bound DppBCDF adopts an inward-facing conformation, similar to that of apo-DppBCDF, with only one ATPγS or AMPPNP molecule bound to DppF. By contrast, ATPγS-bound DppABCDF adopts an outward-facing conformation, with two ATPγS molecules glueing DppD and DppF at the interface. Consistent with structural observations, ATPase activity assays show that the DppBCDF translocator itself is inactive and its activation requires concurrent binding of DppA and ATP. In addition, bacterial complementation experiments imply that a unique periplasmic scoop motif in DppB may play important roles in ensuring dipeptide substrates import across the membrane, presumably by preventing dipeptide back-and-forth binding to DppA and avoiding dipeptides escaping into the periplasm upon being released from DppA.
Sorghum (Sorghum bicolor) is an important food, feed, and fodder crop worldwide and is gaining popularity as an energy crop due to its high potential for biomass production. Some sorghum accessions develop many aerial roots and produce an abundant carbohydrate-rich mucilage after rain. This aerial root mucilage is similar to that observed in landraces of maize (Zea mays) from southern Mexico, which have been previously shown to host diazotrophs. In this study, we characterized the aerial root development of several sorghum accessions and the impact of humidity on this trait. We conducted a microbiome study of the aerial root mucilage of maize and sorghum and isolated numerous diazotrophs from field sorghum mucilage. We observed that the prevailing phyla in the mucilage were Pseudomonadota, Bacteroidota, and Bacillota. However, bacterial abundances varied based on the genotype and the location. Using acetylene reduction,15N2gas feeding, and15N isotope dilution assays, we confirmed that these sorghum accessions can acquire about 40% of their nitrogen from the atmosphere through these associations on aerial roots. Nitrogen fixation in sorghum aerial root mucilage offers a promising avenue to reduce reliance on synthetic fertilizers and promote sustainable agricultural practices for food, feed, fodder, and bioenergy production.
InDrosophila, two interacting adhesion protein families, Defective proboscis responses (Dprs) and Dpr interacting proteins (DIPs), coordinate the assembly of neural networks. While intercellular DIP::Dpr interactions have been well characterized, DIPs and Dprs are often co-expressed within the same cells, raising the question as to whether they also interact incis. We show, in cultured cells and in vivo, that DIP-α and DIP-δ can interact inciswith their ligands, Dpr6/10 and Dpr12, respectively. When co-expressed inciswith their cognate partners, these Dprs regulate the extent oftransbinding, presumably through competitivecisinteractions. We demonstrate the neurodevelopmental effects ofcisinhibition in fly motor neurons and in the mushroom body. We further show that a long disordered region of DIP-α at the C-terminus is required forcisbut nottransinteractions, likely because it alleviates geometric constraints oncisbinding. Thus, the balance betweencisandtransinteractions plays a role in controlling neural development.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting millions worldwide. There is no known cure for AD, highlighting an urgent need for new, innovative treatments. Recent studies have shed light on a promising, noninvasive approach using sensory stimulation as a potential therapy for AD. Exposing patients to light and sound pulses at a frequency of 40 hertz induces brain rhythms in the gamma frequency range that are important for healthy brain activity. Using this treatment in animal models, we are now beginning to understand the molecular, cellular, and circuit-level changes that underlie improvements in disease pathology, cognition, and behavior. A mechanistic understanding of the basic biology that underlies the 40-hertz treatment will inform ongoing clinical trials that offer a promising avenue of treatment without the side effects and high costs typically associated with pharmacological interventions. Concurrent advancements in neurotechnology that can also noninvasively stimulate healthy brain rhythms are illuminating new possibilities for alternative therapies. Altogether, these noninvasive approaches could herald a new era in treating AD, making them a beacon of hope for patients, families, and caregivers facing the challenges of this debilitating condition.
Supergenes can evolve when recombination-suppressing mechanisms like inversions promote co-inheritance of alleles at two or more polymorphic loci that affect a complex trait. Theory shows that such genetic architectures can be favoured under balancing selection or local adaptation in the face of gene flow, but they can also bring costs associated with reduced opportunities for recombination. These costs may in turn be offset by rare ‘gene flux’ between inverted and ancestral haplotypes, with a range of possible outcomes. We aimed to shed light on these processes by investigating the BC supergene, a large genomic region comprising multiple rearrangements associated with three distinct wing colour morphs inDanaus chrysippus, a butterfly known as the African monarch, African queen and plain tiger. Using whole-genome resequencing data from 174 individuals, we first confirm the effects of BC on wing colour pattern: background melanism is associated with SNPs in the promoter region ofyellow, within an inverted subregion of the supergene, while forewing tip pattern is most likely associated with copy-number variation in a separate subregion of the supergene. We then show that haplotype diversity within the supergene is surprisingly extensive: there are at least six divergent haplotype groups that experience suppressed recombination with respect to each other. Despite high divergence between these haplotype groups, we identify an unexpectedly large number of natural recombinant haplotypes. Several of the inferred crossovers occurred between adjacent inversion ‘modules’, while others occurred within inversions. Furthermore, we show that new haplotype groups have arisen through recombination between two pre-existing ones. Specifically, an allele for dark colouration in the promoter ofyellowhas recombined into distinct haplotype backgrounds on at least two separate occasions. Overall, our findings paint a picture of dynamic evolution of supergene haplotypes, fuelled by incomplete recombination suppression.
With the explosive increase in genome sequence data, perhaps the major challenge in natural-product-based drug discovery is the identification of gene clusters most likely to specify new chemistry and bioactivities. We discuss the challenges and state-of-the-art of antibiotic discovery based on ecological principles, genome mining and artificial intelligence.
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Synovial joints, characterized by reciprocally congruent and lubricated articular surfaces separated by a cavity, can simultaneously provide mobility and load bearing. Here, we study the early evolution of synovial joints by examining the morphological, genetic, and molecular features required for the development and function of the joints in elasmobranchs and cyclostomes. We show the presence of cavitated and articulated joints in the skeleton of elasmobranchs, such as the little skate (Leucoraja erinacea) and bamboo shark (Chiloscyllium plagiosum). However, our results do not support the presence of articular cavities between cartilaginous elements in cyclostomes such as sea lampreys (Petromyozon marinus) and hagfish (Myxine glutinosa). Immunostaining reveals the expression of lubrication-related proteoglycans like aggrecan and glycoproteins such as hyaluronic acid receptor (CD44) at the articular surfaces in little skates. Analysis of joint development in little skate embryos shows the expression of growth differentiation factor-5 (Gdf5) andβ-catenin at the joint interzones like tetrapods. Muscle paralysis in little skate embryos leads to joint fusion, suggesting that muscle activity is necessary for the formation of synovial cavity and development of normal articular surfaces, in a manner similar to zebrafish and tetrapods. Together, these data suggest that synovial joints originated in the common ancestor of extant gnathostomes. A review of fossils from the extinct clades along the gnathostome stem suggests that joints with reciprocally articulating surfaces arose in the dermal skeleton of the common ancestor of all jawed vertebrates. Synovial joints in cartilaginous tissue were a subsequent gnathostome innovation.
Cell stress adaptation plays a key role in normal development and in various diseases including cancer. Caspases are activated in response to cell stress, and growing evidence supports their function in non-apoptotic cellular processes. A role for effector caspases in promoting stress-induced cytoprotective autophagy was demonstrated inDrosophila, but has not been explored in the context of human cells. We found a functionally conserved role for effector caspase 3 (CASP3) and caspase 7 (CASP7) in promoting starvation or proteasome inhibition-induced cytoprotective autophagy in human breast cancer cells. The loss of CASP3 and CASP7 resulted in an increase in PARP1 cleavage, reduction in LC3B and ATG7 transcript levels, and a reduction in H2AX phosphorylation, consistent with a block in autophagy and DNA damage-induced stress response pathways. Surprisingly, in non-lethal cell stress conditions, CASP7 underwent non-canonical processing at two calpain cleavage sites flanking a PARP1 exosite, resulting in stable CASP7-p29/p30 fragments. Expression of CASP7-p29/p30 fragment(s) could rescue H2AX phosphorylation in the CASP3 and CASP7 double knockout background. Strikingly, yet consistent with these phenotypes, the loss of CASP3 and CASP7 exhibited synthetic lethality with BRCA1 loss. These findings support a role for human caspases in stress adaptation through PARP1 modulation and reveal new therapeutic avenues for investigation.
Necroptosis initiated by the host sensor Z-NA binding protein 1 (ZBP1) is essential for host defense against a growing number of viruses, including herpes simplex virus 1 (HSV-1). Studies with HSV-1 and other necroptogenic stimuli in murine settings have suggested that ZBP1 triggers necroptosis by directly complexing with the kinase RIPK3. Whether this is also the case in human cells, or whether additional co-factors are needed for ZBP1-mediated necroptosis, is unclear. Here, we show that ZBP1-induced necroptosis in human cells requires RIPK1. We have found that RIPK1 is essential for forming a stable and functional ZBP1-RIPK3 complex in human cells, but is dispensable for the formation of the equivalent murine complex. The receptor-interacting protein (RIP) homology interaction motif (RHIM) in RIPK3 is responsible for this difference between the 2 species, because replacing the RHIM in human RIPK3 with the RHIM from murine RIPK3 is sufficient to overcome the requirement for RIPK1 in human cells. These observations describe a critical mechanistic difference between mice and humans in how ZBP1 engages in necroptosis, with important implications for treating human diseases.
The central nervous system is well-separated from external influences by the blood–brain barrier. Upon surveillance, infection or neuroinflammation, however, peripheral immune cells can enter the brain where they often cause detrimental effects. To invade the brain, immune cells not only have to breach cellular barriers, but they also need to traverse associated extracellular matrix barriers. Neither in vertebrates nor in invertebrates is it fully understood how these processes are molecularly controlled. We recently establishedDrosophila melanogasteras a model to elucidate peripheral immune cell invasion into the brain. Here, we show that neuroinflammation leads to the expression of Unpaired cytokines that activate the JAK/STAT signaling pathway in glial cells of the blood–brain barrier. This in turn triggers the expression of matrix metalloproteinases enabling remodeling of the extracellular matrix enclosing the fly brain and a subsequent invasion of immune cells into the brain. Our study demonstrates conserved mechanisms underlying immune cell invasion of the nervous system in invertebrates and vertebrates and could, thus, further contribute to understanding of JAK/STAT signaling during neuroinflammation.
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Parkinson’s disease (PD) is a neurodegenerative disease characterized by the death of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies that are composed of aggregated α-synuclein (α-Syn). However, the factors that regulate α-Syn pathology and nigrostriatal dopaminergic degeneration remain poorly understood. Previous studies demonstrate cholesterol 24-hydroxylase (CYP46A1) increases the risk for PD. Moreover, 24-hydroxycholesterol (24-OHC), a brain-specific oxysterol that is catalyzed by CYP46A1, is elevated in the cerebrospinal fluid of PD patients. Herein, we show that the levels of CYP46A1 and 24-OHC are elevated in PD patients and increase with age in a mouse model. Overexpression of CYP46A1 intensifies α-Syn pathology, whereas genetic removal of CYP46A1 attenuates α-Syn neurotoxicity and nigrostriatal dopaminergic degeneration in the brain. Moreover, supplementation with exogenous 24-OHC exacerbates the mitochondrial dysfunction induced by α-Syn fibrils. Intracerebral injection of 24-OHC enhances the spread of α-Syn pathology and dopaminergic neurodegeneration via elevated X-box binding protein 1 (XBP1) and lymphocyte-activation gene 3 (LAG3) levels. Thus, elevated CYP46A1 and 24-OHC promote neurotoxicity and the spread of α-Syn via the XBP1–LAG3 axis. Strategies aimed at inhibiting the CYP46A1-24-OHC axis and LAG3 could hold promise as disease-modifying therapies for PD.
Transposons are parasitic genome elements that can also serve as raw material for the evolution of new cellular functions. However, how retrotransposons are selected and domesticated by host organisms to modulate synaptic plasticity remains largely unknown. Here, we show that the Ty1 retrotransposonCopiaforms virus-like capsids in vivo and transfers between cells.Copiais enriched at theDrosophilaneuromuscular junction (NMJ) and transported across synapses, and disrupting its expression promotes both synapse development and structural synaptic plasticity. We show that proper synaptic plasticity is maintained inDrosophilaby the balance ofCopiaand theArc1(activity-regulated cytoskeleton-associated protein) homolog. High-resolution cryogenic-electron microscopy imaging shows that the structure of the Copia capsid has a large capacity and pores like retroviruses but is distinct from domesticated capsids such as dArc1. Our results suggest a fully functional transposon mediates synaptic plasticity, possibly representing an early stage of domestication of a retrotransposon.
Gap junctions allow the exchange of small molecules between cells. How this function could be used to promote cell growth is not yet fully understood. DuringDrosophilaovarian follicle development, germ cells, which are surrounded by epithelial somatic cells, undergo massive growth. We found that this growth depends on gap junctions between these cell populations, with a requirement for Innexin4 and Innexin2, in the germ cells and the somatic cells, respectively. Translatomic analyses revealed that somatic cells express enzymes and transporters involved in amino acid metabolism that are absent in germ cells. Among them, we identified a putative amino acid transporter required for germline growth. Its ectopic expression in the germline can partially compensate for its absence or the one of Innexin2 in somatic cells. Moreover, affecting either gap junctions or the import of some amino acids in somatic cells induces P-bodies in the germ cells, a feature usually associated with an arrest of translation. Finally, in somatic cells, innexin2 expression and gap junction assembly are regulated by the insulin receptor/PI3K kinase pathway, linking the growth of the two tissues. Overall, these results support the view that metabolic transfer through gap junction promotes cell growth and illustrate how such a mechanism can be integrated into a developmental program, coupling growth control by extrinsic systemic signals with the intrinsic coordination between cell populations.
GitHub, a platform widely used in software development, offers a robust framework for documenting all activities of laboratory research projects. This Community Page highlights the benefits of, and provides guidance for, incorporating the GitHub ecosystem into “wet” lab workflows.
Fungi can intervene in hosts’ brain function. In humans, they can drive neuroinflammation, neurodegenerative diseases and psychiatric disorders. However, how fungi alter the host brain is unknown. The mechanism underlying innate immunity to fungi is well-known and universally conserved downstream of shared Toll/TLR receptors, which via the adaptor MyD88 and the transcription factor Dif/NFκB, induce the expression of antimicrobial peptides (AMPs). However, in the brain, Toll-1 could also drive an alternative pathway via Sarm, which causes cell death instead. Sarm is the universal inhibitor of MyD88 and could drive immune evasion. Here, we show that exposure to the fungusBeauveria bassianareduced fly life span, impaired locomotion and caused neurodegeneration.Beauveria bassianaentered theDrosophilabrain and induced the up-regulation ofAMPs, and the Toll adaptorswekandsarm, within the brain. RNAi knockdown ofToll-1, wekorsarmconcomitantly with infection preventedB. bassiana-induced cell loss. By contrast, over-expression ofwekorsarmwas sufficient to cause neuronal loss in the absence of infection. Thus,B. bassianacaused cell loss in the host brain via Toll-1/Wek/Sarm signalling driving immune evasion. A similar activation of Sarm downstream of TLRs upon fungal infections could underlie psychiatric and neurodegenerative diseases in humans.
Tropical forests hold most of Earth’s biodiversity and a higher concentration of threatened mammals than other biomes. As a result, some mammal species persist almost exclusively in protected areas, often within extensively transformed and heavily populated landscapes. Other species depend on remaining remote forested areas with sparse human populations. However, it remains unclear how mammalian communities in tropical forests respond to anthropogenic pressures in the broader landscape in which they are embedded. As governments commit to increasing the extent of global protected areas to prevent further biodiversity loss, identifying the landscape-level conditions supporting wildlife has become essential. Here, we assessed the relationship between mammal communities and anthropogenic threats in the broader landscape. We simultaneously modeled species richness and community occupancy as complementary metrics of community structure, using a state-of-the-art community model parameterized with a standardized pan-tropical data set of 239 mammal species from 37 forests across 3 continents. Forest loss and fragmentation within a 50-km buffer were associated with reduced occupancy in monitored communities, while species richness was unaffected by them. In contrast, landscape-scale human density was associated with reduced mammal richness but not occupancy, suggesting that sensitive species have been extirpated, while remaining taxa are relatively unaffected. Taken together, these results provide evidence of extinction filtering within tropical forests triggered by anthropogenic pressure occurring in the broader landscape. Therefore, existing and new reserves may not achieve the desired biodiversity outcomes without concurrent investment in addressing landscape-scale threats.
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Rodent and human data implicate the hippocampus in the arbitration of approach-avoidance conflict (AAC), which arises when an organism is confronted with a stimulus associated simultaneously with reward and punishment. Yet, the precise contributions of this structure are underexplored, particularly with respect to the decision-making processes involved. We assessed humans with hippocampal damage and matched neurologically healthy controls on a computerized AAC paradigm in which participants first learned whether individual visual images were associated with the reward or loss of game points and were then asked to approach or avoid pairs of stimuli with non-conflicting or conflicting valences. To assess hippocampal involvement more broadly in response conflict, we also administered a Stroop and a Go/No-go task. On the AAC paradigm, following similar learning outcomes in individuals with hippocampal damage and matched controls, both participant groups approached positive and negative image pairs at the same rate but critically, those with hippocampal damage approached conflict pairs more often than controls. Choice and response AAC data were interrogated using the hierarchical drift diffusion model, which revealed that, compared to controls, individuals with hippocampal damage were more biased towards approach, required less evidence to make a decision during conflict trials, and were slower to accumulate evidence towards avoidance when confronted with conflicting image pairs. No significant differences were found between groups in performance accuracy or response time on the response conflict tasks. Taken together, these findings demonstrate the importance of the hippocampus to the evidence accumulation processes supporting value-based decision-making under motivational conflict.
Repetitive stress, a common feature of modern life, is a major risk factor for psychiatric and sensory disorders. Despite the prevalence of perceptual abnormalities in these disorders, little is known about how repetitive stress affects sensory processing and perception. Here, we combine repetitive stress in mice, longitudinal measurement of cortical activity, and auditory-guided behaviors to test if sound processing and perception of neutral sounds in adults are modulated by repetitive stress. We found that repetitive stress alters sound processing, increasing spontaneous cortical activity while dampening sound-evoked responses in pyramidal and PV cells and heightening sound-evoked responses in SST cells. These alterations in auditory processing culminated in perceptual shifts, particularly a reduction in loudness perception. Additionally, our work reveals that the impact of stress on perception evolves gradually as the stressor persists over time, emphasizing the dynamic and evolving nature of this mechanism. Our findings provide insight into a possible mechanism by which repetitive stress alters sensory processing and behavior, challenging the idea that stress primarily modulates emotionally charged stimuli.
In multi-animal tracking, addressing occlusion and crowding is crucial for accurate behavioral analysis. However, in situations where occlusion and crowding generate complex interactions, achieving accurate pose tracking remains challenging. Therefore, we introduced virtual marker tracking (vmTracking), which uses virtual markers for individual identification. Virtual markers are labels derived from conventional markerless multi-animal tracking tools, such as multi-animal DeepLabCut (maDLC) and Social LEAP Estimates Animal Poses (SLEAP). Unlike physical markers, virtual markers exist only within the video and attribute features to individuals, enabling consistent identification throughout the entire video while keeping the animals markerless in reality. Using these markers as cues, annotations were applied to multi-animal videos, and tracking was conducted with single-animal DeepLabCut (saDLC) and SLEAP’s single-animal method. vmTracking minimized manual corrections and annotation frames needed for training, efficiently tackling occlusion and crowding. Experiments tracking multiple mice, fish, and human dancers confirmed vmTracking’s variability and applicability. These findings could enhance the precision and reliability of tracking methods used in the analysis of complex naturalistic and social behaviors in animals, providing a simpler yet more effective solution.
Every mammal studied to date has been found to have a male mutation bias: male parents transmit more de novo mutations to offspring than female parents, contributing increasingly more mutations with age. Although male-biased mutation has been studied for more than 75 years, its causes are still debated. One obstacle to understanding this pattern is its near universality—without variation in mutation bias, it is difficult to find an underlying cause. Here, we present new data on multiple pedigrees from two primate species: aye-ayes (Daubentonia madagascariensis), a member of the strepsirrhine primates, and olive baboons (Papio anubis). In stark contrast to the pattern found across mammals, we find a much larger effect of maternal age than paternal age on mutation rates in the aye-aye. In addition, older aye-aye mothers transmit substantially more mutations than older fathers. We carry out both computational and experimental validation of our results, contrasting them with results from baboons and other primates using the same methodologies. Further, we analyze a set of DNA repair and replication genes to identify candidate mutations that may be responsible for the change in mutation bias observed in aye-ayes. Our results demonstrate that mutation bias is not an immutable trait, but rather one that can evolve between closely related species. Further work on aye-ayes (and possibly other lemuriform primates) should help to explain the molecular basis for sex-biased mutation.
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RNA abundance is controlled by rates of synthesis and degradation. Although mis-regulation of RNA turnover is linked to neurodevelopmental disorders, how it contributes to cortical development is largely unknown. Here, we discover the landscape of RNA stability regulation in the cerebral cortex and demonstrate that intact RNA decay machinery is essential for corticogenesis in vivo. We use SLAM-seq to measure RNA half-lives transcriptome-wide across multiple stages of cortical development. Leveraging these data, we discovercis-acting features associated with RNA stability and probe the relationship between RNA half-life and developmental expression changes. Notably, RNAs that are up-regulated across development tend to be more stable, while down-regulated RNAs are less stable. Using compound mouse genetics, we discover CNOT3, a core component of the CCR4-NOT deadenylase complex linked to neurodevelopmental disease, is essential for cortical development. Conditional knockout ofCnot3in neural progenitors and their progeny in the developing mouse cortex leads to severe microcephaly due to altered cell fate and p53-dependent apoptosis. Finally, we define the molecular targets of CNOT3, revealing it controls expression of poorly expressed, non-optimal mRNAs in the cortex, including cell cycle-related transcripts. Collectively, our findings demonstrate that fine-tuned control of RNA turnover is crucial for brain development.
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AbstractAngiotensensin-converting enzyme-2 (ACE2) is a receptor for SARS-CoV-2, allowing the virus to enter cells. Although tumor patients infected by SARS-CoV-2 often have a worse outcome, the expression, function and clinical relevance of ACE2 in tumors has not yet been thoroughly analyzed. In this study, RNA sequencing (RNA-seq) data from tumors, adjacent tissues and whole blood samples of COVID-19 patients from genome databases and from tumor cell lines and endothelial cells infected with different SARS-CoV-2 variants or transfected with an ACE2 expression vector (ACE2high) or mock (ACE2low) were analyzed for the expression of ACE2 and immune response relevant molecules in silico or by qPCR, flow cytometry, Western blot and/or RNA-seq. The differential expression profiles in ACE2highvs. ACE2lowcells correlated with available SARS-CoV-2 RNA-seq datasets. ACE2highcells demonstrated upregulated mRNA and/or protein levels of HLA class I, programmed death ligand 1 (PD-L1), components of the antigen processing machinery (APM) and the interferon (IFN) signaling pathway compared to ACE2lowcells. Co-cultures of ACE2highcells with peripheral blood mononuclear cells increased immune cell migration and infiltration towards ACE2highcells, apoptosis of ACE2highcells, release of innate immunity-related cytokines and altered NK cell-mediated cytotoxicity. Thus, ACE2 expression was associated in different model systems and upon SARS-CoV-2 infection with an altered host immunogenicity, which might influence the efficacy of immune checkpoint inhibitors. These results provide novel insights into the (patho)physiological role of ACE2 on immune response-relevant mechanisms and suggest an alternative strategy to reduce COVID-19 severity in infected tumor patients targeting the ACE2-induced IFN-PD-L1 axis.
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AbstractThe development of antiviral strategies is a key task of biomedical research, but broad-spectrum virus inhibitors are scarce. Here we show that fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors reduce infection of several cell types with DNA and RNA viruses by blocking early stages of infection, but not viral cell association. Unexpectedly, their antiviral activity was largely independent of FGFR kinase inhibition. RNA profiling showed upregulation of interferon response genes by FGFR inhibitors, but their expression did not correlate with the antiviral activity in infected cells. Using bioinformatics analysis of kinome data, targeted kinase assays, siRNA-mediated knock-down and pharmacological inhibition experiments, we show that blockade of Src family kinases, in particular Lyn, is mainly responsible for the antiviral activity of FGFR inhibitors. These results identify FGFR inhibitors as broad-spectrum antiviral agents and suggest the poorly studied Lyn kinase as a promising target for the treatment of viral infections.
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AbstractSince the late 20th century, researchers have known that caspases are a pillar of cell death, particularly apoptosis. However, recent advances in cell biology have unraveled the multiple roles of caspases. These enzymes have an unconventional role in cell proliferation, differentiation, and invasion. As a result, caspase deregulation can fuel the fire of cancer, incite flames of inflammation, flare neurodegenerative disorders, and exacerbate skin pathologies. Several therapeutic approaches toward caspase inhibition have been investigated, but can caspase inhibitors harness the maladaptive effect of these proteases without causing significant side effects? A few studies have exploited caspase induction for cancer or adoptive cell therapies. Here, we provide a compelling picture of caspases, starting with their evolution, their polytomous roles beyond cell death, the flaws of their deregulation, and the merits of targeting them for therapeutic implications. Furthermore, we provide a deeper understanding of the evolution of caspase-related research up to the current era, pinpointing the role of caspases in cell survival and aiding in the development of effective caspase-targeted therapies.Graphical Abstract
AbstractThe orphan nuclear receptor Nr4a1 has complex biological functions and has been implicated in numerous diseases, including cardiovascular disease. While protective in atherosclerosis and myocardial ischemia, Nr4a1 has been shown to cause cardiac fibrosis in non-ischemic adverse remodeling of the heart. However, mechanisms underlying these actions are still poorly understood. Accordingly, we sought to: (1) understand the contribution of Nr4a1 to the inflammatory environment including macrophage phenotype; and (2) determine the contribution of Nr4a1 to cardiac fibroblast phenotype in the fibrotic heart. Wild type and Nr4a1−/−mice were infused with angiotensin II (1500 ng/kg/min) to induce cardiac fibrosis and diastolic dysfunction. Nr4a1 deletion prevented cardiac fibrosis and maintained normal diastolic function. We determined that macrophages lacking Nr4a1 had distinctly different phenotypes to wild type macrophages, with Nr4a1 deletion preventing the induction of a pro-inflammatory macrophage phenotype, instead promoting an anti-inflammatory phenotype. This had functional consequences in that macrophages lacking Nr4a1 showed a reduced ability to induce cardiac fibroblast migration. Interestingly, deletion of Nr4a1 in isolated cardiac fibroblasts also had profound effects on their phenotype and function, with these cells not able to produce excess extracellular matrix proteins, convert to a myofibroblast phenotype, or respond to macrophage stimuli. Nr4a1 causes cardiac fibrosis and subsequent diastolic dysfunction by inducing a pro-inflammatory phenotype in macrophages and by pushing cardiac fibroblasts towards a pro-fibrotic phenotype in response to pro-fibrotic stimuli. Nr4a1 is also critical for macrophage/fibroblast interactions.
AbstractMTSS1 is a ubiquitously expressed intracellular protein known mainly for its involvement in basic cellular processes, such as the regulation of actin organization and membrane architecture. MTSS1 has attracted much attention for its role as a tumor suppressor, being absent or expressed at reduced levels in advanced and metastasizing cancers. Occasionally, MTSS1 is, instead, upregulated in metastasis and, in some cases, even in primary tumors. In addition to these well-established functions of MTSS1 linked to its I-BAR- and WH2-domains, the protein is involved in modulating cell–cell contacts, cell differentiation, lipid metabolism, and vesicle formation and acts as a scaffolding protein for several E3 ubiquitin ligases. MTSS1 is classified as a housekeeping protein and is never mutated despite the several pathologic phenotypes linked to its dysregulation. Despite MTSS1’s involvement in fundamental signaling pathways, MTSS1 gene ablation is not ubiquitously lethal, although it affects embryonic development. Due to MTSS1´s involvement in many seemingly disparate processes, with many cases lacking mechanistic explanations, we found it timely to review the recent data on MTSS1’s role at the cellular level, as well as in health and disease, to direct further studies on this interesting multifunctional protein.
AbstractX-Linked myotubular myopathy (XLMTM) is characterized by severe skeletal muscle weakness and reduced life expectancy. The pathomechanism and the impact of non-muscular defects affecting survival, such as liver dysfunction, are poorly understood. Here, we investigated organ-specific effects of XLMTM using theMtm1−/ymouse model. We performed RNA-sequencing to identify a common mechanism in different skeletal muscles, and to explore potential phenotypes and compensatory mechanisms in the heart and the liver. The cardiac and hepatic function and structural integrity were assessed both in vivo and in vitro. Our findings revealed no defects in liver function or morphology. A disease signature common to several skeletal muscles highlighted dysregulation of muscle development, inflammation, cell adhesion and oxidative phosphorylation as key pathomechanisms. The heart displayed only mild functional alterations without obvious structural defects. Transcriptomic analyses revealed an opposite dysregulation of mitochondrial function, cell adhesion and beta integrin trafficking pathways in cardiac muscle compared to skeletal muscles. Despite this dysregulation, biochemical and cellular experiments demonstrated that these pathways were strongly affected in skeletal muscle and normal in cardiac muscle. Moreover, biomarkers reflecting the molecular activity of MTM1, such as PtdIns3Pand dynamin 2 levels, were increased in the skeletal muscles but not in cardiac muscle. Overall, these data suggest a compensatory mechanism preserving cardiac function, pointing to potential therapeutic targets to cure the severe skeletal muscle defects in XLMTM.
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AbstractNeurodegenerative disorders such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) affect millions of people worldwide. Curative treatment for these neurodegenerative disorders is still lacking and therefore a further understanding of their cause and progression is urgently needed. Extracellular vesicles (EVs) are nanosized vesicles loaded with cargo, such as proteins and miRNAs, that are released by cells and play an important role in intercellular communication. Intercellular communication through EVs can contribute to the spread of pathological proteins, such as amyloid-beta and tau, or cause pathogenesis through other mechanisms. In addition, EVs may serve as potential biomarkers for diagnosis and for monitoring disease progression. In this review, we summarize and discuss recent advances in our understanding of the role of EVs in AD, ALS an PD with an emphasis on dysregulated cargo in each disease. We highlight shared dysregulated cargo between these diseases, discuss underlying pathways, and outline future implications for therapeutic strategies.
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AbstractPotassium channels encoded byhuman Ether-à-go-go-Related Gene(hERG) are inhibited by diverse cardiac and non-cardiac drugs. Disopyramide is a chiral Class Ia antiarrhythmic that inhibits hERG at clinical concentrations. This study evaluated effects of disopyramide enantiomers on hERG current (IhERG) from hERG expressing HEK 293 cells at 37 °C. S(+) and R(−) disopyramide inhibited wild-type (WT) IhERGwith IC50values of 3.9 µM and 12.9 µM respectively. The attenuated-inactivation mutant N588K had little effect on the action of S(+) disopyramide but the IC50for the R(−) enantiomer was ~ 15-fold that for S(+) disopyramide. The enhanced inactivation mutant N588E only slightly increased the potency of R(−) disopyramide. S6 mutation Y652A reduced S(+) disopyramide potency more than that of R(−) disopyramide (respective IC50values ~ 49-fold and 11-fold their WT controls). The F656A mutation also exerted a stronger effect on S(+) than R(−) disopyramide, albeit with less IC50elevation. A WT-Y652A tandem dimer exhibited a sensitivity to the enantiomers that was intermediate between that of WT and Y652A, suggesting Y652 groups on adjacent subunits contribute to the binding. Moving the Y (normally at site 652) one residue in the N- terminal (up) direction in N588K hERG markedly increased the blocking potency of R(−) disopyramide. Molecular dynamics simulations using a hERG pore model produced different binding modes for S(+) and R(−) disopyramide consistent with the experimental observations. In conclusion, S(+) disopyramide interacts more strongly with S6 aromatic binding residues on hERG than does R(−) disopyramide, whilst optimal binding of the latter is more reliant on intact inactivation.
AbstractThe use of incretin agonists for managing metabolic dysfunction-associated steatohepatitis (MASH) is currently experiencing considerable interest. However, whether these compounds have a direct action on MASH is still under debate. This study aims to investigate whether GLP-1R/GIPR agonists act directly in hepatocytes and hepatic stellate cells (HSCs). For this, human hepatocyte and HSCs lines, as well as primary human hepatocytes and HSCs treated with Liraglutide, Acyl-GIP or the GLP-1/GIP dual agonist (MAR709) were used. We show that the concentrations of each compound, which were effective in insulin release, did not induce discernible alterations in either hepatocytes or HSCs. In hepatocytes displaying elevated fatty acid content after the treatment with oleic acid and palmitic acid, none of the three compounds reduced lipid concentration. Similarly, in HSCs activated with transforming growth factor-β (TGFb), Liraglutide, Acyl-GIP and MAR709 failed to ameliorate the elevated expression of fibrotic markers. The three compounds were also ineffective in phosphorylating CREB, which mediates insulinotropic actions, in both hepatocytes and HSCs. These findings indicate that incretin agonists have no direct actions in human hepatocytes or hepatic stellate cells, suggesting that their beneficial effects in patients with MASH are likely mediated indirectly, potentially through improvements in body weight, insulin resistance and glycemic control.
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AbstractFormins are proteins that catalyze the formation of linear filaments made of actin. INF2, a formin, is crucial for correct vesicular transport, microtubule stability and mitochondrial division. Its activity is regulated by a complex of cyclase-associated protein and lysine-acetylated G-actin (KAc-actin), which helps INF2 adopt an inactive conformation through the association of its N-terminal diaphanous inhibitory domain (DID) with its C-terminal diaphanous autoinhibitory domain. INF2 activation can occur through calmodulin binding, KAc-actin deacetylation, G-actin binding, or association with the Cdc42 GTPase. Mutations in the INF2 DID are linked to focal segmental glomerulosclerosis (FSGS), affecting podocytes, and Charcot-Marie-Tooth disease, which affects Schwann cells and leads to axonal loss. At least 80 pathogenic DID variants of INF2 have been identified, with potential for many more. These mutations disrupt INF2 regulation, leading to excessive actin polymerization. This in turn causes altered intracellular trafficking, abnormal mitochondrial dynamics, and profound transcriptional reprogramming via the MRTF/SRF complex, resulting in mitotic abnormalities and p53-mediated cell death. This sequence of events could be responsible for progressive podocyte loss during glomerular degeneration in FSGS patients. Pharmacological targeting of INF2 or actin polymerization could offer the therapeutic potential to halt the progression of FSGS and improve outcomes for patients with INF2-linked disease.
AbstractBreast carcinoma exhibits the highest incidence among various cancers and is the foremost cause of mortality in women. Increasing evidence shows that SUMOylation of proteins plays a critical role in the progression of breast cancer; however, the role of SENP2 and its molecular mechanism in breast cancer remain underexplored. Here, we discerned that SENP2 promoted the tumorigenesis of breast cancer both in vitro and in vivo. Furthermore, we identified that ERK2 was SUMOylated and that SENP2 played a role by deconjugating ERK2 SUMOylation in breast cancer. SUMOylation of ERK2 promoted its ubiquitin-proteasomal degradation, thus inhibiting the epithelial-to-mesenchymal transition in breast cancer cells. Furthermore, microRNA-145-5p (miR-145-5p) has emerged as a scarce commodity in breast cancer and binds to the 3’-untranslated region of SENP2 mRNA to govern the regulatory dynamics of SENP2 expression. Finally, miR-145-5p inhibits SENP2 transcription, enhances ERK2 SUMOylation, and ultimately suppresses the progression of breast cancer. These revelations suggest evolving ideas for the miR-145-5p-SENP2 axis in therapeutic intervention, thus heralding transformative prospects for the clinical management of breast cancer.
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AbstractEndosomal Sorting Complexes Required for Transport (ESCRTs) are crucial for delivering membrane receptors or intracellular organelles for lysosomal degradation which provides the cell with lysosome-derived nutrients. Yet, how ESCRT dysfunction affects cell metabolism remained elusive. To address this, we analyzed transcriptomes of cells lacking TSG101 or VPS28 proteins, components of ESCRT-I subcomplex. ESCRT-I deficiency reduced the expression of genes encoding enzymes involved in oxidation of fatty acids and amino acids, such as branched-chain amino acids, and increased the expression of genes encoding glycolytic enzymes. The changes in metabolic gene expression were associated with Warburg effect-like metabolic reprogramming that included intracellular accumulation of lipids, increased glucose/glutamine consumption and lactate production. Moreover, depletion of ESCRT-I components led to expansion of the ER and accumulation of small mitochondria, most of which retained proper potential and performed ATP-linked respiration. Mechanistically, the observed transcriptional reprogramming towards glycolysis in the absence of ESCRT-I occurred due to activation of the canonical NFκB and JNK signaling pathways and at least in part by perturbed lysosomal degradation. We propose that by activating the stress signaling pathways ESCRT-I deficiency leads to preferential usage of extracellular nutrients, like glucose and glutamine, for energy production instead of lysosome-derived nutrients, such as fatty acids and branched-chain amino acids.
AbstractPhosphoinositides help steer membrane trafficking routes within eukaryotic cells. In polarized exocytosis, which targets vesicular cargo to sites of polarized growth at the plasma membrane (PM), the two phosphoinositides phosphatidylinositol 4-phosphate (PI4P) and its derivative phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) pave the pathway for vesicle transport from the Golgi to the PM. PI4P is a critical regulator of mechanisms that shape late Golgi membranes for vesicle biogenesis and release. Although enriched in vesicle membranes, PI4P is inexplicably removed from post-Golgi vesicles during their transit to the PM, which drives subsequent steps in exocytosis. At the PM, PI(4,5)P2recruits effectors that establish polarized membrane sites for targeting the vesicular delivery of secretory cargo. The budding yeastSaccharomyces cerevisiaeprovides an elegant model to unravel the complexities of phosphoinositide regulation during polarized exocytosis. Here, we review how PI4P and PI(4,5)P2promote yeast vesicle biogenesis, exocyst complex assembly and vesicle docking at polarized cortical sites, and suggest how these steps might impact related mechanisms of human disease.
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AbstractPain is the hallmark symptom of sickle cell disease (SCD). By adolescence, 20% of youth with SCD develop chronic SCD pain. Our randomized controlled trial found significant reductions in pain in youth receiving digital cognitive-behavioral therapy (CBT) vs education control. However, little is known about factors that moderate the effects of CBT in adolescents with SCD. This secondary data analysis aims to identify adolescent and family characteristics that moderate treatment effects on pain outcomes in 111 adolescents aged 12 to 18 with SCD (M = 14.9, SD = 1.9, girls = 59%) and their caregivers. Adolescents were randomly assigned to digital CBT (N = 57) or education control (N = 54). Digital CBT included separate content for parents/caregivers (ie, a website to learn problem-solving skills and behavioral and communication strategies) and youths (ie, a smartphone app and website to learn pain management skills). Outcomes were assessed at pretreatment, posttreatment (2 months), and follow-up (6 months). Potential moderators included pretreatment variables (ie, adolescent variables: age, executive functioning, anxiety, depression; parent variables: psychological distress, protective behaviors, family functioning). There was a significant overall effect modification on pain intensity outcomes from pretreatment parent psychological distress (P= 0.012), where CBT appeared more effective among those with elevated parental distress. Differential intervention effects were observed across multiple potential moderator groups, though most of these differences did not reach statistical significance. Our study underscores the importance of family factors in understanding the efficacy of digital CBT for adolescent SCD pain, pointing to the need for future research to optimize CBT through targeted family-focused strategies.
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AbstractPain perception varies considerably between and within individuals. How the brain determines these variations has yet to be fully understood. The peak frequency of alpha oscillations has recently been shown to predict an individual's sensitivity to longer-lasting experimental and clinical pain. Peak alpha frequency (PAF) is, thus, discussed as a potential biomarker and novel target for neuromodulatory treatments of pain. Here, we scrutinized the generalizability of the relation between PAF and pain. We applied brief painful laser stimuli to 159 healthy participants and related interindividual and intraindividual variations of pain perception to PAF measured with electroencephalography. Comprehensive multiverse analyses replicated across 2 sessions did not provide consistent evidence for a predictive role of PAF for brief experimental pain. This indicates that the relationship between PAF and pain does not generalize to all types of pain and calls for a systematic exploration of the relationship between PAF, pain perception, and other neuropsychiatric symptoms. Such explorations help to understand the prospects and limits of biomarkers and might guide future research on biomarkers of pain and neuropsychiatric disorders.
AbstractA subset of peripheral sensory neurons expressing specific Mas-related G-protein–coupled receptors and transient receptor potential channels mediate pruritogen-induced chemical itch. However, the molecular mechanisms that regulate the excitability of these cells, and consequently itch sensation, are poorly understood. TWIK-related spinal cord K+channel (TRESK) is a background K+channel that modulates the resting membrane potential, action potential firing, and neuronal excitability, and it has been involved in somatosensation and pain transduction. Here, we demonstrate that this channel contributes to pruritic transduction and it is a potential target for treating chronic itch pathologies. TRESK channel coexpress with Mas-related G-protein-coupled receptor A3, MrgprC11 and MrgprD in mouse sensory neurons, and with MrgprX1 in human ones. Genetic ablation of TRESK enhances firing of MrgprA3-expressing pruriceptors and acute itch in response to intradermal injection of chloroquine, while the response to histamine, BAM8-22, or leukotriene C4 remains unaffected. TRESK deletion also exacerbates chronic itch in mouse models of allergic contact dermatitis, dry skin, and imiquimod-induced psoriasiform dermatitis, resulting in a significantly increased scratching behavior that develops earlier and is more robust. Moreover, pharmacologically enhancing TRESK function diminishes both acute and chronic itch in wild-type mice but not in TRESK knockout (KO) animals. In summary, our data indicate that TRESK plays a role in regulating the excitability of a subset of sensory neurons that mediate histaminergic-independent itch. Enhancing the channel function with specific activators represents a promising antipruritic therapeutic approach that can be combined with other compounds for the treatment of nonhistaminergic itch, which currently lack adequate treatment options.
AbstractAromatase inhibitors (AIs) are crucial for hormone receptor–positive breast cancer patients, enhancing disease-free survival and significantly reducing the risk of distant metastasis and local recurrence. However, AI-induced pain and emotional distress can impair the quality of life and medication adherence, leading to premature discontinuation and increased mortality. In this study, we developed a novel mouse model to investigate these effects. We administered different doses of letrozole to young, artificially menopausal female C57BL/6J mice and assessed pain sensation, emotion-related behaviors, and exercise endurance to identify the optimal AI dose and intervention period. This model was further validated in male and naturally menopausal female mice. Letrozole significantly lowered mechanical pain thresholds in all groups, with the most pronounced pain-related behaviors observed in young, artificially menopausal female mice. Notably, these young female mice also experienced prolonged recovery time postwithdrawal. Aromatase inhibitor–induced anxiety and depressive behaviors were exclusive to young, artificially menopausal female mice and not seen in old naturally menopausal female or young male mice. Serum analysis revealed elevated levels of several proinflammatory cytokines, including interleukin-1β, interferon-γ, tumor necrosis factor-α, and interleukin-6, alongside a reduction in thymocyte counts. Administration of diacerein partially alleviated pain-related behaviors. This model provides a valuable platform for exploring the cellular and molecular mechanisms of AI treatment and evaluating potential therapeutic interventions.
AbstractWhiplash injury is associated with high socioeconomic costs and poor prognosis. Most people are classified as having whiplash-associated disorder grade II (WADII), with neck complaints and musculoskeletal signs, in the absence of frank neurological signs. However, evidence suggests that there is a subgroup with underlying nerve involvement in WADII, such as peripheral neuroinflammation. This study aimed to investigate the presence of neuroinflammation in acute WADII using T2-weighted magnetic resonance imaging of the brachial plexus, dorsal root ganglia and median nerve, and clinical surrogates of neuroinflammation: heightened nerve mechanosensitivity (HNM), raised serum inflammatory mediators, and somatosensory hyperalgesia. One hundred twenty-two WADII participants within 4 weeks of whiplash and 43 healthy controls (HCs) were recruited. Magnetic resonance imaging T2 signal ratio was increased in the C5 root of the brachial plexus and the C5-C8 dorsal root ganglia in WADII participants compared with HCs but not in the distal median nerve trunk. Fifty-five percent of WADII participants had signs of HNM. Inflammatory mediators were also raised compared with HCs, and 47% of WADII participants had somatosensory changes on quantitative sensory testing. In those WADII individuals with HNM, there was hyperalgesia to cold and pressure and an increased proportion of neuropathic pain. Many people with WADII had multiple indicators of neuroinflammation. Overall, our results present a complex phenotypic profile for acute WADII and provide evidence suggestive of peripheral neuroinflammation in a subgroup of individuals. The results suggest that there is a need to reconsider the management of people with WADII.
AbstractImmune cells play a critical role in the transition from acute to chronic pain. However, the role of mast cells in pain remains underinvestigated. Here, we demonstrated that the resolution of inflammatory pain is markedly delayed in mast cell–deficient mice. In response to complete Freund adjuvant, mast cell–deficient mice showed greater levels of nitric oxide, leukocyte infiltration, and altered cytokine/chemokine profile in inflamed skin in both sexes. In wild-type mice, the number of mast cell and mast cell–derived chymases, chymase 1 (CMA1) and mast cell protease 4 (MCPT4), increased in the inflamed skin. Inhibiting chymase enzymatic activity delayed the resolution of inflammatory pain. Consistently, local pharmacological administration of recombinant CMA1 and MCPT4 promoted the resolution of pain hypersensitivity and attenuated the upregulation of cytokines and chemokines under inflammation. We identified CCL9 as a target of MCPT4. Inhibition of CCL9 promoted recruitment of CD206+myeloid cells and alleviated inflammatory pain. Our work reveals a new role of mast cell–derived chymases in preventing the transition from acute to chronic pain and suggests new therapeutic avenues for the treatment of inflammatory pain.
AbstractVirtual reality (VR) is a promising intervention for both experimentally induced and clinical pain, but the factors contributing to the efficacy of VR remain relatively unclear, partially because selecting adequate controls in existing VR studies is challenging. Here, we identified and isolated several factors potentially influencing the hypoalgesic effect of VR. In this within-subjects, counterbalanced controlled study, healthy participants received painful heat stimulation under 5 conditions: VR Ocean (immersive ocean environment), Sham VR Ocean (nonimmersive ocean environment), VR Neutral (immersive neutral environment), Imagination (self-imagined ocean environment), and No-intervention. Participants underwent a pain tolerance test under each condition, stopping the heat stimulation when they reached their maximum tolerance. Participants were also divided into a group with information highlighting the VR Ocean as a highly effective intervention, and a control group receiving no such information. Results showed that pain tolerance, expressed in degree Celsius, was significantly higher in the VR Ocean condition compared with all other conditions, despite VR Ocean not attenuating self-reported pain intensity and disengagement from pain. In addition, VR Ocean decreased pain unpleasantness relative to all conditions except Sham VR Ocean. Virtual reality Ocean also improved mood relative to all other conditions and was perceived as the most engaging. Expectations did not affect the results. Taken together, we found that being immersed in an externally generated pleasant environment is key to the hypoalgesic effect of VR. Virtual reality is effective in increasing the level of pain being tolerated and mitigating the subjective affective experience of pain.
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AbstractPreclinical and epidemiological evidence supports that cannabinoids may have opioid-sparing properties and could be one strategy to decrease opioid use and associated harms like overdose and extramedical use. The objective of this within subjects, double-blind, double-dummy, randomized human laboratory trial was to examine whether cannabidiol (CBD) increases opioid analgesic effects and whether there are corresponding increases in other opioid mediated effects. Healthy participants (N = 31) attended 5 outpatient sessions where they received the following drug conditions: (1) placebo + placebo, (2) 4 mg hydromorphone + placebo, (3) 4 mg hydromorphone + 50 mg CBD, (4) 4 mg hydromorphone + 100 mg CBD, and (5) 4 mg hydromorphone + 200 mg CBD. Before and at multiple time points after drug administration, participants completed (1) quantitative sensory testing, which induced and assessed acute and chronic laboratory models of pain; (2) standard assessments, which queried acute subjective drug effects; and (3) tasks, which assessed psychomotor performance. When combined with a dose of hydromorphone that did not reliably produce analgesic effects on its own, CBD increased the analgesic effects for some laboratory acute pain outcomes but none of the laboratory chronic pain outcomes. At the highest dose of CBD (200 mg), there were concurrent increases in self-report Bad Effects and adverse effects that were not observed at lower doses of CBD (50 mg). Cannabidiol mitigated psychomotor impairment observed with hydromorphone alone. These findings suggest that lower doses of CBD (50 mg) may have utility for enhancing acute analgesic properties of opioids without having corresponding increases in bad effects.
AbstractAs healthcare systems adopt data-driven methods to determine resource allocation for treating low back pain (LBP), it is critical to evaluate equity in time-to-follow-up care after an index visit and long-term occupational outcomes. This retrospective observational study included medical records of 525,252 active duty US service members who received an LBP index diagnosis from June 2016 to February 2022. Poisson generalized additive models evaluated time-to-LBP follow-up visit (primary outcome) and administrative action receipt (eg, disability evaluation; secondary outcome). Service members assigned female in the medical record compared to service members assigned male had lower cumulative hazards of follow-up visit at 1-week, but higher hazards by 4 weeks. Asian and Pacific Islander, Black, and Latino service members compared to white service members had lower cumulative hazards of follow-up visit during the acute/subacute period (up to 7, 19, 31, weeks, respectively), then higher cumulative hazards. Service members whose race and ethnicity was recorded as Other had lower hazards across time. Service members assigned female in the medical record compared to service members assigned male had lower cumulative hazards of administrative action receipt, as did Asian and Pacific Islander, Black, and Latino service members and service members whose race and ethnicity was recorded as Other compared to white service members. Overall, inequities in LBP follow-up visit timing warrant system-level programming to mitigate healthcare barriers acutely and subacutely after an LBP index visit, as well as system-level evaluation of pathways to administration action receipt.
AbstractJuvenile fibromyalgia (JFM) is a chronic pain syndrome predominantly affecting adolescent girls. Resilience may be a protective factor in coping with pain, reducing affective burden, and promoting positive outlooks. Brain regions affected in JFM overlap with those linked to resilience, particularly in the default-mode network (DMN). We investigate the role of resilience on core somatic and affective symptoms in JFM and assess the neurophysiological substrates for the first time. Forty-one girls with JFM and 40 pain-free adolescents completed a resting-state functional magnetic resonance imaging assessment and self-report questionnaires. We used clustering analyses to group JFM participants based on resilience, and principal component analyses to summarize core somatic and affective symptoms. We estimated whole-brain and within-DMN connectivity and assessed differences between higher and lower resilience JFM groups and compared their connectivity patterns to pain-free participants. The higher resilience JFM group had less affective (T = 4.03;P< 0.001) but similar core somatic symptoms (T = 1.05;P= 0.302) than the lower resilience JFM group. They had increased whole-brain (Ts > 4, false discovery rate cluster-level correctedP-value < 0.03) and within-DMN (T = 2.20,P= 0.03) connectivity strength, and higher connectivity between DMN nodes and self-referential and regulatory regions. Conversely, higher DMN-premotor connectivity was observed in the lower resilience group. Juvenile fibromyalgia participants with higher resilience were protected affectively but not in core somatic symptoms. Greater resilience was accompanied by higher signal integration within the DMN, a network central to internally oriented attention and flexible attention shifting. Crucially, the connectivity pattern in highly resilient patients resembled that of pain-free adolescents, which was not the case for the lower resilience group.
AbstractPeripheral sensitization of nociceptors is believed to be a key driver of chronic pain states. Here, we sought to study the effects of a modified version of inflammatory soup on the excitability of human stem cell–derived sensory neurons. For this, we used a preexisting and a novel stem cell line, modified to stably express the calcium sensor GCamP6f. Upon treatment with inflammatory soup, we observed no changes in neuronal transcription or functional responses upon calcium imaging and only a very minor increase in resting membrane potential (RMP) via whole cell patch clamping: control RMP (−71.31 ± 1.1 mV) vs inflammatory soup RMP (−67.74 ± 1.29 mV), uncorrected 2-tailed independent samplesttest,P =0.0383. Similarly, small changes were observed when treating mouse primary sensory neurons with inflammatory soup. A semi-systematic reexamination of past literature further indicated that observed effects of inflammatory mediators on dissociated sensory neuron cultures are generally small. We conclude that modelling inflammation-induced peripheral sensitization in vitro is nontrivial and will require careful selection of mediators and/or more complex, longitudinal multicellular setups. Especially in the latter, our novel GCamP6f-induced pluripotent stem cell line may be of value.
AbstractSpatial pain patterns are widely used as diagnostic tools, yet population-level estimates, such as the prevalence of pain in specific body regions and likelihood of their co-occurrence, are lacking. Despite this, bilateral limb pain is considered relatively uncommon. Baseline data from a population-based Danish cohort were analysed. Twenty-one pain drawing regions, coded as binary “pain”/“no-pain” variables, were entered into an Ising model. Conditional dependencies between pairs of painful regions were quantified, while accounting for the pain state of other regions. Four-week prevalence of pain was also calculated for body regions. Of 4833 analysed pain drawings, 34.7% (1676) reported bilateral (upper or lower) limb pain and 32.3% (1561) reported symmetrical (mirrored) bilateral limb pain. Strongest positive edge weights of the Ising model were between mirrored contralateral regions; the strongest being between left and right hips (mean: 3.86, 95% confidence interval: 3.84-3.87). Next strongest edge weights were between spatially adjacent ipsilateral regions; the strongest being between the right hip and right buttock (mean: 2.72, 95% confidence interval: 2.71-2.74). Negative edge weights, indicating inhibitory relationships, were consistently seen between nonmirrored contralateral regions, the strongest being between regions adjacent to their mirrored contralateral counterparts. In conclusion, bilateral limb pain, particularly in mirrored regions, is more prevalent than previously thought. Pain co-occurrence is facilitated between mirrored contralateral regions and, to a lesser degree, between adjacent ipsilateral regions. An inhibitory effect occurs between nonmirrored contralateral regions, diminishing with increasing distance from the mirrored region. Potential inhibition between mirrored contralateral regions is likely overshadowed by the more dominant facilitation.
AbstractRonald Dubner (1934-2023) was a “giant” in the field of pain. His more than 5 decades of research programs at the US National Institutes of Health and the University of Maryland resulted in important discoveries that considerably advanced our understanding of the neural and nonneural processes underlying acute and chronic pain and their behavioral and clinical correlates. Through his multidisciplinary and translational research approaches, his novel findings as well as his training as a dentist and neuroscientist, Ron was able to bring to the attention of the pain field the clinical implications of these findings and thereby positively influence the clinical management of pain. Also especially notable were his mentorship of numerous pain scientists and clinicians, many of whom went on to develop their own research programs that significantly benefitted the pain field. Ron also played leadership roles in the International Association for the Study of Pain and other scientific organizations, and his editorial positions for thePainjournal significantly and positively influenced the journal's stature and its impact on the pain field. This article, which is part of the journal's series this year that is celebrating its 50th anniversary, highlights Ron's research and related activities during his years at the National Institutes of Health and University of Maryland and includes comments that Ron himself made about these activities. The article also considers his background and personal attributes that underpinned the many contributions that Ron Dubner made to the pain field, including those to the International Association for the Study of Pain andPain.
AbstractPain is not experienced in isolation; it is affected by and affects other people. Interactions between parents and partners and people living with pain affect beliefs, emotions and behaviours, and pain progress and change. We searched systematically for longitudinal studies of associations between specific familial, dyadic, interpersonal factors and quantitative pain transitions. We coded studies for risk of bias. For the narrative synthesis, we grouped findings by dyads—parents and children, and people with pain and their partners (usually spouses), and then by the psychosocial mechanism/s. We described certainty of evidence for each pain transition and each mechanism. Patient and public contributors were involved throughout. Of 52 studies, 38 were of parents and children (27,814 dyads) and 14 of partners (4904 dyads). Three groups of predictive factors were identified for parent and child studies: parent mental health, parent cognitions, and parent behaviours. Parental anxiety (but not depression) predicted children's onset of pain and worsening; the evidence was of moderate certainty and almost exclusively involved mothers. Evidence that some parental behaviours, such as protective behaviours, were associated with worse child pain was of very low certainty. The evidence for partners was of poor quality, precluding synthesis. The review highlights that most interpersonal pain research fails to capture the complex dynamics of longstanding relationships and highlights the difficulty of doing so using simple models.
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AbstractChildren with Christianson syndrome (CS), an X-linked neurodevelopmental disorder caused by loss-of-function mutations in the alkali cation/proton exchanger SLC9A6/NHE6, display severe cognitive impairments, mutism, and sensory abnormalities such as hyposensitivity to pain. However, it is unclear whether these children display other sensory abnormalities and whether their pain hyposensitivity is the result of an elevated pain threshold or a complete insensitivity to pain. To better characterize the sensory abnormalities in this disorder, we used a combination of a mouse model of CS and pain questionnaires directed at nonverbal patients with CS. We recruited 14 young male participants with CS and subjected them to a novel observational tool, the Pain Sensory and Painful Situations Questionnaire (PSQ), which takes multiple painful situations into account to broaden the description of pain expression. By analyzing social expressive behaviours of pain in these nonverbal patients, the PSQ documented that over 60% of the participants were unaffected by mechanical or inflammatory painful stimuli. This reduced pain sensitivity was also observed in the mouse CS model. Surprisingly, CS mice also displayed aversive reactions to innocuous stimuli, which prompted us to examine whether such reactions were also present in children with CS. Indeed, the results from the PSQ revealed that 30% to 50% of these patients showed an aversive response to normally innocuous stimuli like light touch and gusts of air. Our results demonstrate that children with CS have aversive reactions to innocuous stimuli and are hyposensitive to painful stimuli, the latter making them at risk for developing complications from unreported injuries.
AbstractDysmenorrhea affects as much as 85% of female youth in Canada and the United States and can negatively impact academic performance, overall health, and mental well-being. The physician–patient relationship can play an important role in supporting patients with pain conditions, such as dysmenorrhea. Through effective communication, trust, and validation, physician–patient interactions can empower pain patients, potentially improving pain outcomes. To date, no studies have quantitatively examined the impact of physician–patient interactions on youth's experiences of dysmenorrhea. Therefore, our aim was to explore the relationships among perceived physician communication, pain invalidation, trust in the physician, treatment adherence, menstrual sensitivity, and dysmenorrhea symptom severity among emerging adults (EA) and test a conceptual model of potential interactions using partial least squares structural equation modeling (PLS-SEM). The online survey was administered to Canadian and American EA aged 18 to 21 (Mage= 19.4,SD= 1.1) years with dysmenorrhea. Two models were tested using PLS-SEM: model A only included participants who had received a treatment plan from their physician (n = 279) and model B included the full data set (N = 362). In both models, the perception of more effective physician communication and reduced pain invalidation were related to lower dysmenorrhea symptom severity through menstrual sensitivity. In model A, better physician communication and lower pain invalidation were also associated with higher reported treatment adherence by trust in the physician; however, neither treatment adherence nor trust in the physician were associated with dysmenorrhea symptom severity. Future research should include additional elements within the clinical encounter and further refine the model.
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AbstractPreclinical studies suggested that Transient Receptor Potential Vanilloid 1 (TRPV1) channels contribute to neuropathic pain in animal models of diabetic polyneuropathy. Patients with painful diabetic polyneuropathy commonly experience ongoing burning pain. This study aimed at evaluating the association between this specific type of pain and TRPV1 intraepidermal nerve fibers in patients with painful diabetic polyneuropathy. We consecutively enrolled 70 patients with diabetic polyneuropathy. Each patient completed the Neuropathic Pain Symptom Inventory (NPSI) to identify the various types of neuropathic pain. All patients underwent a distal leg skin biopsy, with immunostaining of skin nerve fibers using antibodies for the pan-axonal marker Protein Gene Product 9.5 (PGP9.5), TRPV1, Calcitonin Gene-Related Peptide (CGRP), and Substance P. We found that 57% of patients (n = 40) had neuropathic pain symptoms, with ongoing burning pain being the most frequently reported type of pain at the NPSI (70% of patients with pain, n = 28). Patients with ongoing burning pain had higher TRPV1 intraepidermal nerve fiber density and TRPV1/PGP9.5 ratio compared with those with painless polyneuropathy (P= 0.014,P= 0.013) and painful polyneuropathy with other types of pain (P< 0.0001,P= 0.024); they also had increased CGRP dermal nerve fiber density compared with patients with painless polyneuropathy (P= 0.005). Our study showed that ongoing burning pain is associated with an increased expression of intraepidermal TRPV1 fibers, as well as an increased dermal representation of CGRP fibers. These findings suggest that TRPV1 contributes to ongoing burning pain, possibly in conjunction with elevated CGRP expression, highlighting its significance as a therapeutic target for patients with painful diabetic polyneuropathy.
AbstractDegeneration of peripheral nerves causes neuropathic pain. Previous studies have documented structural and functional brain alterations in peripheral neuropathy, which may be attributed to maladaptive plasticity following chronic neuropathic pain. Nevertheless, the effects of peripheral neuropathic pain on the macroscale organization of the cerebral cortex have not been explored. This study investigated altered surface morphology and topographic hierarchy of the cerebral cortex in patients with neuropathic pain due to peripheral neuropathy. T1-weighted magnetic resonance imaging data were acquired from 52 patients with peripheral neuropathic pain and 50 age- and sex-matched healthy controls. Cortical morphometric features including thickness and gyrification index were obtained using surface-based morphometry. A topographic gradient encoding interregional similarity in cortical thickness was extracted using a machine-learning technique named diffusion map embedding. Compared with controls, patients with neuropathic pain exhibited cortical thinning in the frontal and sensorimotor cortices, with the severity increasing with greater neuropathic pain. The patients also showed decreased gyrification in the insula, with a greater reduction in gyrification linked to more severe skin nerve degeneration. Moreover, the patients exhibited altered topographic organization of the cerebral cortex, where the direction of the topographic gradient deviated from the occipital-to-frontal axis observed in the controls in this study and reported in the literature. Our findings provided a novel perspective for macroscale cortical structural reorganization after neuropathic pain, showing thinning and gyral flattening in pain-related areas and deviation from the normal topographic axis of the cerebral cortex.
AbstractThe risk-benefit ratio of perioperative opioid analgesia is controversial. Few studies have analyzed the effectiveness of opioids in the early postoperative period. To analyze the effectiveness of early opioid administration in this period in a large number of surgeries in routine care, we compared pain-related outcomes between patients treated on wards with different rates of early opioid administration. In this observational study, we analyzed data from 111,693 patients in 392 surgical wards between 2010 and 2022 within the German Quality Improvement in Postoperative Pain Management registry. We defined early opioid administration at the ward-level as the percentage of patients who received at least 1 opioid dose between the end of surgery and data collection on the first postoperative day, including recovery room and ward. To identify different patterns of early opioid administration, we considered these percentages in patients with mild, moderate, and severe pain and appliedk-means clustering. We performed mixed regression analyses to assess associations between clusters and patient-reported outcomes on the first postoperative day. At the ward-level, the median percentage of early opioid administration was 79.5% (first-third quartile: 64.5%-92.0%), and 2 clusters of wards were identified. In clusters 1 and 2, an opioid was administered in 58.5% and 89.0% of patients, respectively. Patients in cluster 2 reported better outcomes for pain intensity and pain-related interference but worse outcomes for nausea. However, the effect sizes were small. Patients treated on surgical wards with a higher rate of early opioid administration reported slightly better pain-related outcomes on the first postoperative day.
AbstractPain perception is a dynamic and time-varying phenomenon. The high temporal resolution of electroencephalography (EEG) can be leveraged to gain insight into its cortical dynamics. Electroencephalography microstate analysis is a novel technique that parses multichannel EEG signals into a limited number of quasi-stable topographies (microstates) that have a meaningful temporal structure and have been linked to the activity of resting state networks. In recent years, several studies have investigated alterations in EEG microstate parameters associated with acute and chronic pain states, with mixed results. In the present study, we used high-frequency stimulation (HFS), in healthy human volunteers, to induce mechanical hypersensitivity (a perceptual correlate of central sensitization) and investigated (1) changes in microstate parameters before vs after the induction of mechanical hypersensitivity and (2) whether microstate parameters before HFS were linked to the development of mechanical hypersensitivity. Results showed that the duration of microstate E, typically related to the activity of the salience/default mode network, was consistently decreased post-HFS. The global explained variance of microstates A (Auditory network) and E and coverage of microstate A were positively associated with mechanical hypersensitivity. Conversely, the transition probabilities from microstates B (Visual network) to A and the bidirectional transition probabilities between B and C (saliency and default mode networks) were negatively associated with mechanical hypersensitivity. We discuss these findings in the context of the functional significance of EEG microstates. Our results highlight the potential utility of microstate analysis in understanding pain processing and its potential link to changes in the nociceptive system.
AbstractTranscranial focused ultrasound (tFUS) is an emerging noninvasive neuromodulation technology that has shown great potential in pain modulation. This review systematically elucidates the multilevel biological mechanisms of tFUS neuromodulation, from network-wide effects to cellular and molecular processes, as well as broader systemic influences. Preliminary animal pain model studies have revealed tFUS's ability to improve pain behavioral indicators and modulate neural circuit activity under pathological conditions. A small number of clinical studies also suggest that tFUS may have certain benefits in improving symptom experience and emotional state in chronic pain patients. However, current research generally has limitations such as small sample sizes and short follow-up periods. More high-quality studies are needed to verify the long-term effects and safety of tFUS pain treatment. Overcoming these limitations and advancing large-scale clinical translational research will help fully exploit the application potential of tFUS in precision pain medicine and provide new treatment options for pain relief.
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AbstractPain clinical trials are notoriously complex and often inefficient in demonstrating efficacy, even for known efficacious treatments. A major issue is the difficulty in the a priori identification of specific phenotypes to include in the study population. Recent work has identified the extent of widespread pain as an important determinant of the likelihood of response to therapy, but it has not been tested in clinical trials for the treatment of interstitial cystitis/bladder pain syndrome (IC/BPS). We explored this hypothesis using data from 3 previously published trials testing treatments for IC/BPS, which suggested modest benefits but did not meet a priori primary outcome statistical significance criteria. Importantly, these studies also collected symptom questionnaire data that allowed us to retrospectively identify participants with and without widespread pain. Analyzing the treatment by the degree of widespread pain revealed a difference in outcome and statistical significance level for each trial. Participants with predominately local pain (ie, limited widespread pain symptoms) responded to therapy targeting local symptoms, whereas those with widespread pain did not. Alternatively, participants with widespread pain beyond their local pelvic pain responded to more centrally acting treatments. Our results suggest that differentiating patients based on widespread vs more localized pain is a key consideration for designing future clinical trials for conditions with variable pain profiles, such as IC/BPS and potentially other pain-based syndromic disorders.
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AbstractLarge-scale GWAS studies have uncovered hundreds of genomic loci linked to facial and brain shape variation, but only tens associated with cranial vault shape, a largely overlooked aspect of the craniofacial complex. Surrounding the neocortex, the cranial vault plays a central role during craniofacial development and understanding its genetics are pivotal for understanding craniofacial conditions. Experimental biology and prior genetic studies have generated a wealth of knowledge that presents opportunities to aid further genetic discovery efforts. Here, we use the conditional FDR method to leverage GWAS data of facial shape, brain shape, and bone mineral density to enhance SNP discovery for cranial vault shape. This approach identified 120 independent genomic loci at 1% FDR, nearly tripling the number discovered through unconditioned analysis and implicating crucial craniofacial transcription factors and signaling pathways. These results significantly advance our genetic understanding of cranial vault shape and craniofacial development more broadly.
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AbstractChromosome Conformation Capture (3 C) methods, including Hi-C (a high-throughput variation of 3 C), detect pairwise interactions between DNA regions, enabling the reconstruction of chromatin architecture in the nucleus. HiChIP is a modification of the Hi-C experiment that includes a chromatin immunoprecipitation (ChIP) step, allowing genome-wide identification of chromatin contacts mediated by a protein of interest. In mammalian cells, cohesin protein complex is one of the major players in the establishment of chromatin loops. We present an improved cohesin HiChIP experimental protocol. Using comprehensive bioinformatic analysis, we show that a dual chromatin fixation method compared to the standard formaldehyde-only method, results in a substantially better signal-to-noise ratio, increased ChIP efficiency and improved detection of chromatin loops and architectural stripes. Additionally, we propose an automated pipeline called nf-HiChIP (https://github.com/SFGLab/hichip-nf-pipeline) for processing HiChIP samples starting from raw sequencing reads data and ending with a set of significant chromatin interactions (loops), which allows efficient and timely analysis of multiple samples in parallel, without requiring additional ChIP-seq experiments. Finally, using advanced approaches for biophysical modelling and stripe calling we generate accurate loop extrusion polymer models for a region of interest and provide a detailed picture of architectural stripes, respectively.
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AbstractPhenological mismatches and resource limitations resulting from ongoing environmental change can have severe impacts on pollinator fitness. Recent findings show that bumblebee workers respond to pollen scarcity by damaging plant leaves in ways that can accelerate flowering, suggesting a mechanism by which direct information transfer from bees to plants might influence the timing of flower production. However, the ecological and adaptive significance of this interaction remains uncertain. Here we report that mated and unmated queens ofBombus terrestrisalso damage leaves, with similar effects on flowering. Furthermore, we document leaf damage by wild-caught queens from 12 species, spanning seven subgenera, indicating damaging behavior is widespread amongBombusspecies. Leaf damage by bumblebee queens may have particular relevance in the context of colony founding and early development, where the timely availability of local floral resources can be critical for colony success and fitness.
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AbstractMicropterigidae is regarded as the sister group of all the other Lepidoptera, providing important insights into the evolution of Lepidoptera. However, the gene and protein profiles of silk from Micropterigidae have not yet been identified. In this study, we investigate the components of silk cocoons of the micropterigid speciesNeomicropteryx cornuta. Here we show that the protein fibroin heavy chain (FibH) is absent in the silk ofN. cornutaand that the putative homolog of fibroin light chain (FibL) is also absent or severely altered. This is confirmed by transcriptome and genome analyses of the conserved regions in this species. The examination of the synteny around thefibHgenes in several Lepidoptera and Trichoptera species shows that the genomic region containing this gene is absent in another micropterigid species,Micropterix aruncella. In contrast, we found putative orthologs offibHandfibLin the representative transcripts of another distinct clade, Eriocraniidae. This study shows that the loss of FibH and the loss or severe divergence of FibL occurrs specifically in the family Micropterigidae and reveals dynamic evolutionary changes in silk composition during the early evolution of Lepidoptera. It also shows that silk proteins without FibH can form a solid cocoon.
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AbstractUnderstanding insomnia is crucial for improving its diagnosis and treatment. However, many subjective complaints about insomnia do not align with objective measures of sleep quality, as is the case in subjective-objective sleep discrepancy (SOSD). We address this discrepancy by measuring sleep intrusions and instability in polysomnographic recordings from a large clinical database. Using machine learning, we develop personalized models to infer hypnodensities—a continuous and probabilistic measure of sleep dynamics—, and analyze them via information theory to measure intrusions and instability in a principled way. We find that insomnia with SOSD involves sleep intrusions during intra-sleep wakefulness, while insomnia without SOSD shows wake intrusions during sleep, indicating distinct etiologies. By mapping these metrics to standard sleep features, we provide a continuous and interpretable framework for measuring sleep quality. This approach integrates and values subjective insomnia complaints with physiological data for a more accurate view of sleep quality and its disorders.
AbstractStructure-based drug design aims to create active compounds with favorable properties by analyzing target structures. Recently, deep generative models have facilitated structure-specific molecular generation. However, many methods are limited by inadequate pharmaceutical data, resulting in suboptimal molecular properties and unstable conformations. Additionally, these approaches often overlook binding pocket interactions and struggle with selective inhibitor design. To address these challenges, we developed a framework called Coarse-grained and Multi-dimensional Data-driven molecular generation (CMD-GEN). CMD-GEN bridges ligand-protein complexes with drug-like molecules by utilizing coarse-grained pharmacophore points sampled from diffusion model, enriching training data. Through a hierarchical architecture, it decomposes three-dimensional molecule generation within the pocket into pharmacophore point sampling, chemical structure generation, and conformation alignment, mitigating instability issues. CMD-GEN outperforms other methods in benchmark tests and controls drug-likeness effectively. Furthermore, CMD-GEN excels in cases across three synthetic lethal targets, and wet-lab validation with PARP1/2 inhibitors confirms its potential in selective inhibitor design.
AbstractLoss of epithelial cell polarity and tissue disorganization are hallmarks of carcinogenesis, in which Ca2+signaling plays a significant role. Here we demonstrate that the plasma membrane Ca2+pump PMCA4 (ATP2B4) is downregulated in luminal breast cancer, and this is associated with shorter relapse-free survival in patients with luminal A and B1 subtype tumors. Using the MCF-7 breast cancer cell model we show that PMCA4 silencing results in the loss of cell polarity while a forced increase in PMCA4b expression induces cell polarization and promotes lumen formation. We identify Arf6 as a regulator of PMCA4b endocytic recycling essential for PMCA4-mediated lumen formation. Silencing of the singlepmcagene inDrosophila melanogasterlarval salivary gland destroys lumen morphology suggesting a conserved role of PMCAs in lumen morphogenesis. Our findings point to a role of PMCA4 in controlling epithelial cell polarity, and in the maintenance of normal glandular tissue architecture.
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AbstractDimensionality reduction greatly facilitates the exploration of cellular heterogeneity in single-cell RNA sequencing data. While most of such approaches are data-driven, it can be useful to incorporate biologically plausible assumptions about the underlying structure or the experimental design. We propose the boosting autoencoder (BAE) approach, which combines the advantages of unsupervised deep learning for dimensionality reduction and boosting for formalizing assumptions. Specifically, our approach selects small sets of genes that explain latent dimensions. As illustrative applications, we explore the diversity of neural cell identities and temporal patterns of embryonic development.
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AbstractWater kefir (WK) is an artisanal fermented beverage made from sugary water, optional fruits and WK grains. WK grains can be reused to start new fermentations. Here we investigate the microbial composition and function of 69 WK grains and their ferments by shotgun metagenomics. A subset of samples was subjected to metabolomic, including volatilomic, analysis. The impact of different fermentation practices on microbial composition and fermentation characteristics was analysed and it was noted that, for example, the common practice of drying water kefir grains significantly reduces microbial diversity and negatively impacts subsequent grain growth. Metagenomic analysis allowed the detection of 96 species within WK, the definition of core genera and the detection of different community states after 48 h of fermentation. A total of 485 bacterial metagenome assembled genomes were obtained and 18 putatively novel species were predicted. Metabolite and volatile analysis show associations between key species with flavour compounds. We show the complex microbial composition of WK and links between fermentation practices, microbes and the fermented product. The results can be used as a foundation for the selection of species for large scale WK production with desired flavour profiles and to guide the regulatory framework for commercial WK production.
AbstractThe transition towards the brain state induced by psychedelic drugs is frequently neglected in favor of a static description of their acute effects. We use a time-dependent whole-brain model to reproduce large-scale brain dynamics measured with fMRI from 15 volunteers under 20 mg intravenous N,N-Dimethyltryptamine (DMT), a short-acting psychedelic. To capture its transient effects, we parametrize the proximity to a global bifurcation using a pharmacokinetic equation. Simulated perturbations reveal a transient of heightened reactivity concentrated in fronto-parietal regions and visual cortices, correlated with serotonin 5HT2a receptor density, the primary target of psychedelics. These advances suggest a mechanism to explain key features of the psychedelic state and also predicts that the temporal evolution of these features aligns with pharmacokinetics. Our results contribute to understanding how psychedelics introduce a transient where minimal perturbations can achieve a maximal effect, shedding light on how short psychedelic episodes may extend an overarching influence over time.
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ABSTRACTAstrocytes are the most abundant glial cell type in the central nervous system (CNS). Astrocytes are born during the early postnatal period in the rodent brain and mature alongside neurons, demonstrating remarkable morphological structural complexity, which is attained in the second postnatal month. Throughout this period of development and across the remainder of the lifespan, astrocytes participate in CNS homeostasis, support neuronal partners, and contribute to nearly all aspects of CNS function. In the present study, we analyzed astrocyte gene expression in the cortex of wild‐type male rodents throughout their lifespan (postnatal 7 days to 18 months). A pairwise timepoint comparison of differential gene expression during early development and CNS maturation (7–60 days) revealed four unique astrocyte gene clusters, each with hundreds of genes, which demonstrate unique temporal profiles. These clusters are distinctively related to cell division, cell morphology, cellular communication, and vascular structure and regulation. A similar analysis across adulthood and in the aging brain (3 to 18 months) identified similar patterns of grouped gene expression related to cell metabolism and cell structure. Additionally, our analysis identified that during the aging process astrocytes demonstrate a bias toward shorter transcripts, with loss of longer genes related to synapse development and a significant increase in shorter transcripts related to immune regulation and the response to DNA damage. Our study highlights the critical role that astrocytes play in maintaining CNS function throughout life and reveals molecular shifts that occur during development and aging in the cortex of male mice.
ABSTRACTChronic neuroinflammation, driven by central nervous system (CNS)‐resident astrocytes and microglia, as well as infiltration of the peripheral immune system, is an important pathologic mechanism across a range of neurologic diseases. For decades, research focused almost exclusively on how neuroinflammation impacted neuronal function; however, there is accumulating evidence that injury to the oligodendrocyte lineage is an important component for both pathologic and clinical outcomes. While oligodendrocytes are able to undergo an endogenous repair process known as remyelination, this process becomes inefficient and usually fails in the presence of sustained inflammation. The present review focuses on our current knowledge regarding activation of the innate and adaptive immune systems in the chronic demyelinating disease, multiple sclerosis, and provides evidence that sustained neuroinflammation in other neurologic conditions, such as perinatal white matter injury, traumatic brain injury, and viral infections, converges on oligodendrocyte injury. Lastly, the therapeutic potential of targeting the impact of inflammation on the oligodendrocyte lineage in these diseases is discussed.
ABSTRACTIn multiple sclerosis (MS), an influx of immune cells into the central nervous system leads to focal demyelinating lesions in the brain, optic nerve, and spinal cord. As MS progresses, remyelination increasingly fails, leaving neuronal axons vulnerable to degeneration and resulting in permanent neurological disability. In chronic MS lesions, the aberrant accumulation of extracellular matrix (ECM) molecules, including fibronectin and hyaluronan, impairs oligodendrocyte progenitor cell differentiation, contributing to remyelination failure. Removing inhibitory ECM is therefore a therapeutic target to stimulate remyelination in MS. Intriguingly, the expression of the fibronectin‐degrading enzyme matrix metalloproteinase 7 (MMP7) is decreased in chronic MS lesions compared to control white matter. Therefore, we examined the role of MMP7 upon cuprizone‐induced demyelination, hypothesizing that the lack of MMP7 would lead to impaired breakdown of its ECM substrates, including fibronectin, and diminished remyelination. Unexpectedly, remyelination proceeded efficiently in the absence of MMP7. In the remyelination phase, the lack of MMP7 did not lead to the accumulation of fibronectin or of laminin, another MMP7 substrate. Moreover, in the setting of chronic demyelination, levels of fibronectin were actually lower in MMP7−/−mice, while levels of hyaluronan, which is not a known MMP7 substrate, were also lower. Overall, these results indicate that MMP7 is not essential for remyelination in the cuprizone model and point to an unexpected complexity in how MMP7 deficiency influences fibronectin and hyaluronan levels in chronic demyelination.
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ABSTRACTChromatin remodeling complexes (CRCs) participate in oligodendrocyte (OL) differentiation, survival, and maintenance. We asked whether CRCs also control the proliferation of OL precursors (OPs)—focusing on the INO80 complex, which is known to regulate the proliferation of a variety of other cell types during development and disease. CRISPR/Cas9‐mediated inactivation ofIno80in vitro, or Cre‐mediated deletion in vivo, slowed the OP cell cycle substantially by prolonging G1. RNAseq analysis revealed that E2F target genes were dysregulated in OPs from INO80‐deficient mice, but correlated RNAseq and ATAC‐seq uncovered no general correlation between gene expression and altered nucleosome positioning at transcription start sites. Fluorescence photobleaching experiments in cultured OPs demonstrated that histone H2A.Z mobility increased following the loss of INO80, suggesting that INO80 regulates the cell cycle machinery in OPs through H2A.Z/H2A exchange. We also present evidence that INO80 associates with OLIG2, a master regulator of OL development.
ABSTRACTAlzheimer's disease (AD) is the most prevalent neurodegenerative disease, characterized by memory decline and behavioral changes. Its pathological features include senile plaques, neurofibrillary tangles, and reactive gliosis, comprising abnormal accumulations of β‐amyloid peptide (Aβ) and hyperphosphorylated tau protein surrounded by reactive astrocytes and microglia. Recently, it has emerged that severe reactive astrocytes and MAOB‐dependent production of GABA and H2O2are the real causes of learning and memory impairment and neurodegeneration. Diverse mouse models for AD have been developed to clarify pathological mechanisms and discover therapeutic strategies and drugs. However, there are many shortfalls and discrepancies among them. A new AD mouse model named FAD4Thas been developed to overcome various shortcomings. Here, we employed astrocyte‐focused screening procedures to examine the pathological features of FAD4Tas an AD model. Our results revealed that the FAD4Tmice showed abnormal accumulation of Aβ plaques in overall brain regions at 6 and 12 months. We found astrocytic hypertrophy with a significant elevation of GFAP and LCN2. However, the expressions of MAOB and iNOS, a severe reactive astrocyte marker, were unchanged. Electrophysiological and behavioral analysis indicated aberrant tonic GABA release, reduced neuronal activity, and impaired CA1‐specific memory. These findings demonstrate that FAD4Tmice mimic pathological and functional features of AD, different from other AD mouse models. These findings demonstrate that FAD4Tmimics some features of AD patients but lacks other important features, such as severe reactive astrocytes and neurodegeneration. This astrocyte‐focused screening method offers valuable tools for advancing AD research and developing new therapeutic strategies.
ABSTRACTThe function of microglia during progression of Alzheimer's disease (AD) can be investigated using mouse models that enable genetic manipulation of microglial subpopulations in a temporal manner. We developed mouse lines that express either Cre recombinase (Cre) for constitutive targeting, or destabilized‐domain Cre recombinase (DD‐Cre) for inducible targeting from theCst7locus (Cst7DD‐Cre) to specifically manipulate disease associated microglia (DAM) and crossed with Ai14 tdTomato cre‐reporter line mice. Cst7Crewas found to target all brain resident myeloid cells, due to transient developmental expression of Cst7, but no expression was found in the inducibleCst7DD‐Cremice. Further crossing of this line with 5xFAD mice combined with dietary administration of trimethoprim to induce DD‐Cre activity produces long‐term labeling in DAM without evidence of leakiness, with tdTomato‐expression restricted to cells surrounding plaques. Using this model, we found that DAMs are a subset of plaque‐associated microglia (PAMs) and their transition to DAM increases with age and disease stage. Spatial transcriptomic analysis revealed that tdTomato+ cells show higher expression of disease and inflammatory genes compared to other microglial populations, including non‐labeled PAMs. These models allow either complete cre‐loxP targeting of all brain myeloid cells (Cst7Cre), or inducible targeting of DAMs, without leakiness (Cst7DD‐Cre).
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ABSTRACTThe myelination is a critical process during brain development. This study aimed to explore the impact of volatile anesthetic sevoflurane on developing myelination and the role of microglial activation in this process. Neonatal C57BL/6J mice were exposed to sevoflurane at their postnatal 6–8 days. Neurobehavioral tests were used to assess fine motor and cognitive functions. Myelination of hippocampus (HC) and corpus callosum (CC), as well as microglial activation, were determined by western blotting and immunostaining. Lipid droplets were assessed by Oil‐Red‐O and Bodipy staining. Further, primary microglia were co‐cultured with oligodendrocyte precursor cell (OPC) to determine the role of microglia in the proliferation and differentiation of OPC. And microglial inhibitor minocycline and CSF1R inhibitor PLX5622 were administered to assess the effects of microglial activation on developing myelination. The results showed that repeated sevoflurane exposure impaired both fine motor and cognitive functions and induced abnormal expressions of myelin‐related proteins myelin basic protein (MBP) and platelet‐derived growth factor α receptor (PDGFR‐α). And accumulations of lipid droplets were found in the microglia of HC and CC after sevoflurane exposure. Further, the spatiotemporal response to repeated sevoflurane exposure in glial cells exhibited an aberrant myelination process and microglial polarization. The conditioned medium from sevoflurane‐treated microglia inhibited the OPC proliferation and differentiation, while minocycline or PLX5622 alleviated sevoflurane‐induced neuroinflammation and hypomyelination. Therefore, repeated sevoflurane exposure negatively affected OPC differentiation and myelination trajectory through hyperactivating microglia in developing brain, leading to motor and cognitive impairments, while microglial inhibition/depletion could protect against sevoflurane‐induced damage on developing myelination.
ABSTRACTInflammation‐induced oligodendrocyte death and CNS demyelination are key features of multiple sclerosis (MS). Inflammation‐triggered endoplasmic reticulum (ER) stress and oxidative stress promote tissue damage in MS and in its preclinical animal model, experimental autoimmune encephalitis (EAE). Compound AA147 is a potent activator of the ATF6 signaling arm of the unfolded protein response (UPR) that can also induce antioxidant signaling through activation of the NRF2 pathway in neuronal cells. Previous work showed that AA147 protects multiple tissues against ischemia/reperfusion damage through ATF6 and/or NRF2 activation; however, its therapeutic potential in neuroinflammatory disorders remains unexplored. Here, we demonstrate that AA147 ameliorated the clinical symptoms of EAE and reduced ER stress, oligodendrocyte loss, and demyelination. Additionally, AA147 suppressed T cells in the CNS without altering the peripheral immune response. Importantly, AA147 significantly increased the expressions ofGrp78, an ATF6 target gene, in oligodendrocytes, while enhancing levels ofGrp78as well asHo‐1, an NRF2 target gene, in microglia. In cultured oligodendrocytes, AA147 promoted nuclear translocation of ATF6, but not NRF2. Intriguingly, AA147 altered the microglia activation profile, possibly by triggering the NRF2 pathway. AA147 was not therapeutically beneficial during the acute EAE stage in mice lacking ATF6 in oligodendrocytes, indicating that protection primarily involves ATF6 activation in these cells. Overall, our results suggest AA147 as a potential therapeutic opportunity for MS by promoting oligodendrocyte survival and regulating microglia status through distinct mechanisms.
ABSTRACTThe Fragile X Messenger Ribonucleoprotein (FMRP) is an RNA binding protein that regulates the translation of multiple mRNAs and is expressed by neurons and glia in the mammalian brain. Loss of FMRP leads to fragile X syndrome (FXS), a common inherited form of intellectual disability and autism. While most research has been focusing on the neuronal contribution to FXS pathophysiology, the role of glia, particularly oligodendrocytes, is largely unknown. FXS individuals are characterized by white matter changes, which imply impairments in oligodendrocyte differentiation and myelination. We hypothesized that FMRP regulates oligodendrocyte maturation and myelination during postnatal development. Using a combination of human pluripotent stem cell—derived oligodendrocytes and anFmr1knockout rat model, we studied the role of FMRP on mammalian oligodendrocyte development. We found that the loss of FMRP leads to shared defects in oligodendrocyte morphology in both rat and human systems in vitro, which persist in the presence of FMRP‐expressing axons in chimeric engraftment models. Our findings point to species‐conserved, cell‐autonomous defects during oligodendrocyte maturation in FXS.
ABSTRACTIbudilast, an inhibitor of macrophage migration inhibitory factor (MIF) and phosphodiesterase (PDE), has been recently shown to have neuroprotective effects in a variety of neurologic diseases. We utilize a chick excitotoxic retinal damage model to investigate ibudilast's potential to protect retinal neurons. Using single cell RNA‐sequencing (scRNA‐seq), we find that MIF, putative MIF receptors CD74 and CD44, and several PDEs are upregulated in different retinal cells during damage. Intravitreal ibudilast is well tolerated in the eye and causes no evidence of toxicity. Ibudilast effectively protects neurons in the inner nuclear layer from NMDA‐induced cell death, restores retinal layer thickness on spectral domain optical coherence tomography (SD‐OCT), and preserves retinal neuron function, particularly for the ON bipolar cells, as assessed by electroretinography. PDE inhibition seems essential for ibudilast's neuroprotection, as AV1013, the analogue that lacks PDE inhibitor activity, is ineffective. scRNA‐seq analysis reveals upregulation of multiple signaling pathways, including mTOR, in damaged Müller glia (MG) with ibudilast treatment compared to AV1013. Components of mTORC1 and mTORC2 are upregulated in both bipolar cells and MG with ibudilast. The mTOR inhibitor rapamycin blocked accumulation of pS6 but did not reduce TUNEL positive dying cells. Additionally, through ligand‐receptor interaction analysis, crosstalk between bipolar cells and MG may be important for neuroprotection. We have identified several paracrine signaling pathways that are known to contribute to cell survival and neuroprotection and might play essential roles in ibudilast function. These findings highlight ibudilast's potential to protect inner retinal neurons during damage and show promise for future clinical translation.
ABSTRACTGlial cells were first defined by Rudolf Virchow in 1856. About 40 years later, glial research had developed into a field distinct from the mainstream study of neurons as the central elements governing brain function. By that time, substantial knowledge about the properties of glial cells had accumulated, exemplified by five important publications by four distinguished investigators: Gustav Retzius, Michael von Lenhossek, Carl Weigert, and Hans Held. These treatises broadly summarized what was known about glial cells, comparing findings from leeches to humans. Practically speaking, these articles represent the foundation of our current knowledge. All five contributions were published in German, which at the time was one of the dominant languages for scientific exchange. This article summarizes and comments on their findings and thus provides insight into what was known about glial cells at that time. More importantly, in the Supporting Information, we provide English translations and original scans of these five publications, making them accessible to an international readership.
ABSTRACTParkinson's disease (PD) is characterized by the degeneration of dopaminergic nigrostriatal inputs, which causes striatal network dysfunction and leads to pronounced motor deficits. Recent evidence highlights astrocytes as a potential local source for striatal neuromodulation. There is substantial evidence for norepinephrine‐mediated recruitment of cortical astrocyte activity during movement and locomotion. However, it is unclear how astrocytes in the striatum, a region devoid of norepinephrine neuromodulatory inputs, respond during locomotion. Moreover, it remains unknown how dopamine loss affects striatal astrocyte activity and whether astrocyte activity regulates behavioral deficits in PD. We addressed these questions by performing astrocyte‐specific calcium recordings and manipulations using in vivo fiber photometry and chemogenetics. We find that locomotion elicits astrocyte calcium activity over a slower timescale than neurons. Acute pharmacological blockade of dopamine receptors only moderately reduced locomotion‐related astrocyte activity. Yet, unilateral dopamine depletion significantly attenuated astrocyte calcium responses. Chemogenetic stimulation of Gi‐coupled receptors partially improved this functional astrocyte deficit in dopamine‐lesioned mice. In parallel, chemogenetic manipulation restored asymmetrical motor deficits and moderately improved open‐field exploratory behavior. Together, our results establish a novel role for functional striatal astrocyte signaling in modulating motor function in PD and highlight non‐neuronal targets for potential PD therapeutics.
ABSTRACTReactive astrocytes are associated with Alzheimer's disease (AD), and several AD genetic risk variants are associated with genes highly expressed in astrocytes. However, the contribution of genetic risk within astrocytes to cellular processes relevant to the pathogenesis of AD remains ill‐defined. Here, we present a resource for studying AD genetic risk in astrocytes using a large collection of induced pluripotent stem cell (iPSC) lines from deeply phenotyped individuals with a range of neuropathological and cognitive outcomes. IPSC lines from 44 individuals were differentiated into astrocytes followed by unbiased molecular profiling using RNA sequencing and tandem mass tag‐mass spectrometry. We demonstrate the utility of this resource in examining gene‐ and pathway‐level associations with clinical and neuropathological traits, as well as in analyzing genetic risk and resilience factors through parallel analyses of iPSC‐astrocytes and brain tissue from the same individuals. Our analyses reveal that genes and pathways altered in iPSC‐derived astrocytes from individuals with AD are concordantly dysregulated in AD brain tissue. This includes increased levels of prefoldin proteins, extracellular matrix factors, COPI‐mediated trafficking components and reduced levels of proteins involved in cellular respiration and fatty acid oxidation. Additionally, iPSC‐derived astrocytes from individuals resilient to high AD neuropathology show elevated basal levels of interferon response proteins and increased secretion of interferon gamma. Correspondingly, higher polygenic risk scores for AD are associated with lower levels of interferon response proteins in astrocytes. This study establishes an experimental system that integrates genetic information with a matched iPSC lines and brain tissue data from a large cohort of individuals to identify genetic contributions to molecular pathways affecting AD risk and resilience.
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ABSTRACTGlia antigen‐presenting cells (APCs) are pivotal regulators of immune surveillance within the retina, maintaining tissue homeostasis and promptly responding to insults. However, the intricate mechanisms underlying their local coordination and activation remain unclear. Our study integrates an animal model of retinal injury, retrospective analysis of human retinas, and in vitro experiments to gain insights into the crucial role of antigen presentation in neuroimmunology during retinal degeneration (RD), uncovering the involvement of various glial cells, notably Müller glia and microglia. Glial cells act as sentinels, detecting antigens released during degeneration and interacting with T‐cells via MHC molecules, which are essential for immune responses. Microglia function as APCs via the MHC Class II pathway, upregulating key molecules such as Csf1r and cytokines. In contrast, Müller cells act through the MHC Class I pathway, exhibiting upregulated antigen processing genes and promoting a CD8+T‐cell response. Distinct cytokine signaling pathways, including TNF‐α and IFN Type I, contribute to the immune balance. Human retinal specimens corroborate these findings, demonstrating glial activation and MHC expression correlating with degenerative changes. In vitro assays also confirmed differential T‐cell migration responses to activated microglia and Müller cells, highlighting their role in shaping the immune milieu within the retina. In summary, our study emphasizes the involvement of retinal glial cells in modulating the immune response after insults to the retinal parenchyma. Unraveling the intricacies of glia‐mediated antigen presentation in RD is essential for developing precise therapeutic interventions for retinal pathologies.
ABSTRACTNeuromyelitis optica spectrum disorders (NMOSD) are severe autoimmune conditions affecting the central nervous system. In a subset of cases, no autoantibodies are detectable with the currently used routine assays. This study aimed to determine whether the levels of expression of aquaporin‐4 (AQP4), excitatory amino acid transporter 2 (EAAT2), or complement C3/C3d and C5b‐9 in human astrocytes following incubation with patient sera under inflammatory conditions differ between the various NMOSD subtypes and whether such differences can help to identify autoantibody‐mediated cases of NMOSD. Levels of AQP4, EAAT2, complement C3/C3d and C5b‐9 epitope expression on human astrocytes pretreated with various cytokines were quantitatively analyzed via indirect immunofluorescence after exposure to sera from patients with AQP4‐IgG seropositive, MOG‐IgG seropositive, and AQP4/MOG‐IgG double seronegative NMOSD. Significant differences in AQP4 and C3d epitope expression were observed, with IL‐17A, IL‐10, and IL‐6 pre‐treatment notably influencing astrocytic responses. Using uniform manifold approximation and projection (UMAP), patients were classified into clusters corresponding to AQP4‐IgG seropositive, MOG‐IgG seropositive, or double seronegative NMOSD. These results demonstrate distinct astrocytic staining patterns across NMOSD subtypes, providing a potential diagnostic tool for distinguishing between autoantibody‐mediated astrocytopathy and other cases. These findings suggest specific pathogenic mechanisms linked to each NMOSD subtype, which may have implications for tailoring therapeutic strategies based on cytokine involvement and astrocyte reactivity.
ABSTRACTAutism spectrum disorder (ASD) is marked by neurobehavioral developmental deficits, potentially linked to disrupted neuron–glia interactions. The astroglia Kir4.1 channel plays a vital role in regulating potassium levels during neuronal activation, and mutations in this channel have been associated with ASD. This study investigates astroglia Kir4.1 as a regulator of neuronal excitability and behavioral abnormalities in rats with autistic‐like traits induced by prenatal exposure to valproic acid (VPA). Whole‐cell patch‐clamp recordings were obtained from pyramidal neurons in the hippocampal CA1 region, showing that inhibition of Kir4.1 channels led to electrophysiological changes indicative of neuronal hyperexcitability, similar to that seen in VPA‐exposed neurons. Specifically, there was increased input resistance and voltage threshold, alongside decreased time constant and rheobase. Behavioral assessments after 7 days of intrahippocampal PA6 (5 μg/mL/day) administration revealed significant social withdrawal, heightened anxiety, reduced exploration, and impaired recognition memory, underscoring the behavioral deficits linked to autism. While Kir4.1 inhibition affected excitability, it did not alter the output of CA1 pyramidal neurons in autistic‐like rats. These findings emphasize the critical role of astroglia Kir4.1 channels in modulating neuronal excitability and associated behavioral impairments within the VPA‐induced autism model, suggesting a promising target for future therapeutic interventions.
ABSTRACTMicroglia, the parenchymal macrophage of the central nervous system, serve crucial remodeling functions throughout development. Microglia are transcriptionally heterogenous, suggesting that distinct microglial states confer discrete roles. Currently, little is known about how dynamic these states are, the cues that promote them, or how they impact microglial function. In the developing retina, we previously found a significant proportion of microglia express CD11c (Integrin αX,Itgax,subunit of complement receptor 4) which has also been reported in other developmental and disease contexts. Here, we sought to understand the regulation and function of CD11c+ microglia. We found that CD11c+ microglia track with prominent waves of neuronal apoptosis in postnatal retina. Using genetic fate mapping, we provide evidence that microglia transition out of the CD11c state to return to homeostasis. We show that CD11c+ microglia have elevated lysosomal content and contribute to the clearance of apoptotic neurons, and found that acquisition of CD11c expression is partially dependent upon the TAM receptor AXL. Using selective ablation, we found CD11c+ microglia are not uniquely critical for phagocytic clearance of apoptotic cells. Together, our data suggest that CD11c+ microglia are a transient state induced by developmental apoptosis rather than a specialized subset mediating phagocytic elimination.
ABSTRACTManipulating wound healing‐associated signaling after SCI presents a promising avenue for increasing the recovery of function after injury. This study explores the potential of targeting molecular regulators of wound healing, initially identified in nonneural tissues, to enhance outcomes after SCI. Astrocytes, pivotal in central nervous system wound healing, play a crucial role in tissue remodeling and recovery. However, the optimal manipulation of astrogliosis for beneficial outcomes remains elusive. Previous research demonstrated a transcriptional response in astrocytes resembling epithelial‐to‐mesenchymal transitions (EMTs) after CNS injury. Here, we investigate the extrinsic manipulation of wound healing through the Receptor Activator of Nuclear‐factor Kappa‐Β (RANK) pathway, known for its involvement in nonneural tissue remodeling and linked to EMT pathway. Using a severe thoracic spinal cord contusion mouse model, we demonstrate that acute activation of the RANK pathway with RANK ligand (RANKL) adversely affects tissue remodeling, resulting in larger lesion volumes and delayed recovery of posture and locomotion. These findings suggest that early perturbations in the tight molecular regulation of tissue remodeling negatively impact the wound‐healing process after SCI. The study provides a proof‐of‐concept demonstration that exogenous nonneural remodeling ligands can modify astrocyte responses and functional recovery after SCI, raising questions about the optimal time frame for beneficial remodeling interventions during injury progression. These insights open new avenues for therapeutic strategies aimed at improving functional outcomes following SCI.
ABSTRACTAt cellular and circuit levels, drug addiction is considered a dysregulation of synaptic plasticity. In addition, dysfunction of the glutamate transporter 1 (GLT‐1) in the nucleus accumbens (NAc) has also been proposed as a mechanism underlying drug addiction. However, the cellular and synaptic impact of GLT‐1 alterations in the NAc remain unclear. Here we show in the NAc that 10 days withdraw after 5 days treatment with cocaine or amphetamine decreases GLT‐1 expression in astrocytes, which results in the prolongation of the excitatory postsynaptic potential (EPSP) decay kinetics in D1 receptor‐containing medium spiny neurons (D1R‐MSNs). Using the spike timing dependent plasticity (STDP) paradigm, we found that enlargement of EPSP duration results in switching the LTP elicited in control animals to LTD in psychostimulant‐treated mice. In contrast to D1‐MSNs, D2‐MSNs did not display changes in EPSP kinetics and synaptic plasticity. Notably, the psychostimulant‐induced synaptic transmission and synaptic plasticity effects were absent in IP3R2−/−mice, which lack astrocyte calcium signal, but were mimicked by the selective astrocytes stimulation with DREADDs. Finally, ceftriaxone, which upregulates GLT‐1, restored normal GLT‐1 function, EPSP kinetics, and synaptic plasticity in psychostimulant‐treated mice. Therefore, we propose that cocaine and amphetamine increase dopaminergic levels in the NAc, which stimulates astrocytes and downregulates the GLT‐1. The decreased GLT‐1 function prolonged the EPSP kinetics, leading to the modulation of the STDP, transforming the LTP observed in control animals into LTD in psychostimulant‐treated mice. Present work reveals a novel mechanism underlying the synaptic plasticity changes induced by these drugs of abuse.
ABSTRACTEmerging evidence indicates that astrocytes modulate energy metabolism and homeostasis. However, one important but poorly understood element is the necessity of astrocytes in the control of body weight. Here, we apply viral vector‐assisted brain‐region selective loss of astrocytes to define physiological roles played by astrocytes in the arcuate nucleus of the hypothalamus (ARH) and to elucidate the involved mechanism. We find that astrocyte loss potently augments body weight in adult mice fed chow or high‐fat diet. Mechanistically, we find that the loss of astrocytes reduces adipose tissue norepinephrine (NE) contents and chemogenetic stimulation of adipose tissue sympathetic inputs reverses the astrocyte loss‐induced increase in body weight. Collectively, our findings in this study suggest a crucial physiological role of astrocytes in preventing diet‐induced energy surfeit and obesity by modulating adipose tissue lipid metabolism through central sympathetic outflows to adipose tissues.
ABSTRACTAstrocytes are the most abundant type of macroglia in the brain and play crucial roles in regulating neural development and functions. The diverse functions of astrocytes are largely determined by their morphology, which is regulated by genetic and environmental factors. However, whether and how the astrocyte morphology is affected by temperature remains largely unknown. Here we discovered that elevated cultivation temperature (26°C) stimulatesCaenorhabditis elegansventral CEPsh glia endfoot extension during early developmental stages. This extension depends on the activation of glutamate AWC neurons, which inhibit the postsynaptic cholinergic AIY interneurons through glutamate‐gated chloride channels, GLC‐3 and GLC‐4. In responding to the thermosensory signal, the guanyl‐nucleotide exchange factor EPHX‐1 and Rho GTPase CDC‐42/Cdc42 in the glia facilitate the endfoot extension via F‐actin assembly. This study elucidates the significant role of thermosensory circuitry in glia morphogenesis and the underlying molecular mechanism.
ABSTRACTMicroglia play a critical role in maintaining central nervous system (CNS) homeostasis and display remarkable plasticity in their response to inflammatory stimuli. However, the specific signaling profiles that microglia adopt during such challenges remain incompletely understood. Traditional transcriptomic approaches provide valuable insights, but fail to capture dynamic post‐translational changes. In this study, we utilized time‐resolved single‐cell mass cytometry (CyTOF) to measure distinct signaling pathways activated in microglia upon exposure to bacterial and viral mimetics—lipopolysaccharide (LPS) and polyinosinic‐polycytidylic acid (Poly(I:C)), respectively. Furthermore, we evaluated the immunomodulatory role of astrocytes on microglial signaling in mixed cultures. Microglia or mixed cultures derived from neonatal mice were treated with LPS or Poly(I:C) for 48 h. Cultures were stained with a panel of 33 metal‐conjugated antibodies targeting signaling and identity markers. High‐dimensional clustering analysis was used to identify emergent signaling modules. We found that LPS treatment led to more robust early activation of pp38, pERK, pRSK, and pCREB compared to Poly(I:C). Despite these differences, both LPS and Poly(I:C) upregulated the classical reactivity markers CD40 and CD86 at later time points. Strikingly, the presence of astrocytes significantly blunted microglial responses to both stimuli, particularly dampening CD40 upregulation. Our studies demonstrate that single‐cell mass cytometry effectively captures the dynamic signaling landscape of microglia under pro‐inflammatory conditions. This approach may pave the way for targeted therapeutic investigations of various neuroinflammatory disorders. Moreover, our findings underscore the necessity of considering cellular context, such as astrocyte presence, in interpreting microglial behavior during inflammation.
The P-type pentatricopeptide repeat (PPR) proteins are crucial for RNA editing and post-transcriptional regulation in plant organelles, particularly mitochondria. This study investigates the role of OsPPR674 in rice, focusing on its function in mitochondrial RNA editing. Using CRISPR/Cas9 technology, we generated ppr674 mutant and examined its phenotypic and molecular characteristics. The results indicate that ppr674 exhibits reduced plant height, decreased seed-setting rate, and poor drought tolerance. Further analysis revealed that in the ppr674 mutant, RNA editing at the 299th nucleotide position of the mitochondrial ccmC gene (C-to-U conversion) was abolished. REMSAs showed that GST-PPR674 specifically binds to RNA probes targeting this ccmC-299 site, confirming its role in this editing process. In summary, these results suggest that OsPPR674 plays a pivotal role in mitochondrial RNA editing, emphasizing the significance of PPR proteins in organelle function and plant development.
Therapeutic efficacy of histidyl dipeptides such as carnosine is hampered by circulating carnosinase-1 (CN1), which catalyzes carnosine’s hydrolysis and degradation. Prior reports suggest that oral carnosine may improve cardiometabolic parameters in patients with heart failure (HF), but whether CN1 activity is affected by HF is unknown. Here, we measured CN1 content and carnosine degradation rate (CDR) in preoperative plasma samples from a cohort of patients (n = 138) undergoing elective cardiac surgery to determine whether plasma CN1 and/or CDR varied with left ventricular (LV) systolic dysfunction. CN1 content was normally distributed in the cohort, but plasma CDR displayed a quasi-bimodal distribution into high- (>2 nmol/(h*μL)) and low-activity (≤2 nmol/(h*μL)) clusters. Multivariable analysis confirmed female sex, diabetes and LV systolic dysfunction was associated with the low-activity CDR cluster. Although CN1 content did not differ, logistic regression analysis revealed that CDR and CN1-specific activity (CDR/CN1 content) was significantly lower in patients with both moderate (ejection fraction, EF ≥ 35 to <50%) and severe LV systolic dysfunction (EF < 35%) compared with patients in the normal range (EF ≥ 50%). These findings suggest that plasma CN1 activity is regulated by factors independent of expression, and that a decline in LV systolic function is associated with low CN1 activity. Further studies are needed to delineate specific mechanisms controlling CN1 expression and activity, which will facilitate the development of carnosine and other histidyl dipeptide therapies for cardiometabolic disorders such as HF.
Endometrial cancer is the fourth most common cancer in women in Europe. Its carcinogenesis is a complex process and requires further research. In our study, we focus on finding new and easy-to-diagnose markers for detecting endometrial cancer. For this purpose, we compared the levels of miR-21-5p, miR-205-5p, and miR-222-3p in endometrial cancer tissues with the levels of these miRs in the serum of patients using the dPCR method. Our study is preliminary and consists of comparing the changes in miRNA expression in serum to the changes in miRNA in tissue of patients with endometrial cancer. The study included 18 patients with EC and 19 patients undergoing surgery for pelvic organ prolapse or uterine fibroids as a control group without neoplastic lesions. Endometrial tissue and serum were collected from all patients. The analyses showed an increased expression of miR-205-5p in endometrial cancer tissue and decreased expression of miR-222-3p in tissue and serum samples. These results suggest that miR-205-5p and miR-222-3p may be potential endometrial cancer biomarkers. Only miR-222-3p confirmed its decreased expression in serum, making it a potential and easily accessible marker in the diagnosis of endometrial cancer. This pilot study requires further investigation in a larger group of patients. Its advantages include the possibility of a comparison between miRNA expression in tissue and serum, as well as conducting the study using dPCR.
Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant inherited neurodegenerative disease caused by the expansion of glutamine (Q)-encoding CAG repeats in the gene ATAXIN1 (ATXN1). Patients with SCA1 suffer from movement and cognitive deficits and severe cerebellar pathology. Previous studies identified sex differences in disease progression in SCA1 patients, but whether these differences are present in mouse models is unclear. Using a battery of behavioral tests, immunohistochemistry of brain slices, and RNA sequencing, we examined sex differences in motor and cognitive performance, cerebellar pathology, and cerebellar gene expression changes in a recently created conditional knock-in mouse model f-ATXN1146Q expressing human coding regions of ATXN1 with 146 CAG repeats. We found worse motor performance and weight loss accompanied by increased microglial activation and an increase in immune viral response pathways in male f-ATXN1146Q mice.
The epididymis represents a pivotal organ for sperm maturation and male fertility maintenance. During the epididymal journey, sperm cells undergo morphological and molecular changes that need to acquire the morpho-functional skills necessary for successful oocyte fertilization. Not last, a great enrichment of the spermatozoa RNA payload occurs via an epithelium-derived epididymosome transfer. Currently, circular RNAs (circRNAs), a class of non-coding RNAs (ncRNAs), are acquiring a prominent role in the setting of sperm quality parameters. In this regard, they are considered potential targets in several male infertility conditions. Despite their consolidated role, few notions are known regarding the alleged epididymal backsplicing activity. In the current review, we discuss the main aspects of spermatozoa maturation along the epididymis and the circRNA role in the field of male reproduction. We also report the most recent findings on the circRNA biogenesis that occurs in the epididymal duct, providing new fascinating evidence on epididymal-derived circRNAs. Finally, we show preliminary compelling data on epididymal backsplicing by exploiting the experimental mouse model of aging. Collectively, these data evidence a remarkable role of the epididymis in remodeling the circRNA payload and in shaping its profile in maturating spermatozoa.
Lupus nephritis (LN), a significant complication of systemic lupus erythematosus (SLE), represents a challenging manifestation of the disease. One of the prominent pathophysiologic mechanisms targeting the renal parenchyma is fibrosis, a terminal process resulting in irreversible tissue damage that eventually leads to a decline in renal function and/or end-stage kidney disease (ESKD). Both glomerulosclerosis and interstitial fibrosis emerge as reliable prognostic indicators of renal outcomes. This article reviews the hallmarks of renal fibrosis in lupus nephritis, including the known and putative drivers of fibrogenesis. A better understanding of the cellular and molecular processes driving fibrosis in LN may help inform the development of therapeutic strategies for this disease, as well as the identification of individuals at higher risk of developing ESKD.
Cullin 2 (Cul2), a core component of the Cullin-RING E3 ubiquitin ligase complex, is integral to regulating distinct biological processes. However, its role in innate immune defenses remains poorly understood. In this study, we investigated the functional significance of Cul2 in the immune deficiency (IMD) signaling-mediated antimicrobial immune reactions in Drosophila melanogaster (fruit fly). We demonstrated that loss-of-function of Cul2 led to a marked reduction in antimicrobial peptide induction following bacterial infection, which was associated with increased fly mortality and bacterial load. The proteomic analysis further revealed that loss-of-function of Cul2 reduced the expression of Effete (Eff), a key E2 ubiquitin-conjugating enzyme during IMD signaling. Intriguingly, ectopic expression of eff effectively rescued the immune defects caused by loss of Cul2. Taken together, the results of our study underscore the critical role of Cul2 in ensuring robust IMD signaling activation, highlighting its importance in the innate immune defense against microbial infection in Drosophila.
Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape for several malignancies, but their efficacy in unresectable pancreatic adenocarcinoma remains uncertain. This systematic review aimed to evaluate the effectiveness and safety of ICIs in this context, focusing on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicity. A comprehensive search of MEDLINE, EMBASE, CENTRAL, and Scopus identified 34 eligible studies, including randomized controlled trials and observational cohorts. Quantitative synthesis involved 21 studies comprising 937 patients, with additional qualitative analyses on biomarker-driven subgroups and early-phase trials. The median OS across studies was 8.65 months, while the median PFS was 2.55 months. The ORR and DCR were 16.2% and 50.3%, respectively, with grade ≥3 treatment-related adverse events occurring in 22% of patients. Promising outcomes were observed in MSI-H/dMMR populations, although these represented only 1–2% of cases. Combination strategies with chemotherapy demonstrated synergistic potential but lacked definitive evidence due to heterogeneity and the absence of phase III trials. ICIs showed a manageable toxicity profile, highlighting their feasibility in selected patients. Future research should focus on overcoming tumor microenvironment barriers and identifying biomarkers to optimize responsiveness and expand the applicability of ICIs in pancreatic cancer.
Hypoxic stress causes cell damage and serious diseases in organisms, especially in aquatic animals. It is important to elucidate the changes in metabolic function caused by hypoxia and the mechanisms underlying these changes. This study focuses on the low oxygen tolerance feature of a new blunt snout bream strain (GBSBF1). Our data show that GBSBF1 has a different lipid and carbohydrate metabolism pattern than wild-type bream, with altering glycolysis and lipid synthesis. In GBSBF1, the expression levels of phd2 and vhl genes are significantly decreased, while the activation of HIF-3α protein is observed to have risen significantly. The results indicate that enhanced HIF-3α can positively regulate gpd1ab and gpam through PPAR-γ, which increases glucose metabolism and reduces lipolysis of GBSBF1. This research is beneficial for creating new aquaculture strains with low oxygen tolerance traits.
In recent years there has been a resurgent interest in plant products as substitutes for animal-derived food products, in which legumes, including peas, feature highly. Here, we report on a set of Pisum sativum L. (pea) near-isolines, comprising 24 unique mutants at five loci, where the impact of the mutations on the corresponding enzymes of the starch pathway confers a wrinkled-seeded phenotype. Together with a set of round-seeded mutants impacted at a sixth locus, all 27 mutants show variation for starch composition and protein content. The mutations have been mapped onto three-dimensional protein models to examine potential effects on the corresponding enzyme structures and their activities, and to guide targeted mutagenesis. The mutant lines represent a unique suite of alleles for rapid introduction into elite pea varieties to create new materials for the food and feed markets and industrial applications.
Perfluorooctane sulfonic acid (PFOS) is a persistent organic pollutant that has attracted much attention due to its wide environmental distribution and potential toxicity. Intestinal microbiota is an important regulator of host health, and its composition and metabolic function are easily interfered with by environmental pollutants. In this study, the effects of PFOS exposure on gut microbiota, lipid metabolism, and host health were investigated in mice. The results showed that PFOS exposure did not significantly change α diversity, but significantly affected the β diversity and community structure of intestinal microflora in mice. At the taxonomic level, the ratio of Firmicutes to Bacteroidetes decreased, and the changes in the abundance of specific bacteria were closely related to liver diseases and lipid metabolism disorders. PFOS exposure also interfered with the gut–liver axis mechanism, increased blood lipids and liver function related indicators in mice, and induced intestinal and liver histological lesions. This study revealed the toxic mechanism of PFOS mediated by intestinal microbiota, providing a new research perspective for health problems caused by environmental pollutants and theoretical support for the formulation of relevant public health policies.
Autophagy is a critical mechanism by which methamphetamine (METH) induces neuronal damage and neurotoxicity. Prolonged METH exposure can result in the accumulation of autophagosomes within cells. The autophagy process encompasses several essential vesicle-related biological steps, collectively referred to as the autophagic flux. However, the precise mechanisms by which METH modulates the autophagic flux and the underlying pathways remain to be elucidated. In this study, we utilized a chronic METH exposure mouse model and cell model to demonstrate that METH treatment leads to an increase in p62 and LC3B-II and the accumulation of autophagosomes in striatal neurons and SH-SY5Y cells. To assess autophagic flux, this study utilized autophagy inhibitors and inducers. The results demonstrated that the lysosomal inhibitor chloroquine exacerbated autophagosome accumulation; however, blocking autophagosome formation with 3-methyladenine did not prevent METH-induced autophagosome accumulation. Compared to the autophagy activator rapamycin, METH significantly reduced autophagosome–lysosome fusion, leading to autophagosome accumulation. Rab7a is a critical regulator of autophagosome–lysosome fusion. Although Rab7a expression was upregulated in SH-SY5Y cells and brain tissues after METH treatment, immunoprecipitation experiments revealed weakened interactions between Rab7a and the lysosomal protein RILP. Overexpression of active Rab7a (Rab7a Q67L) significantly alleviated the METH-induced upregulation of LC3-II and p62. PTEN, a key regulator of Rab7a dephosphorylation, was downregulated following METH treatment, resulting in decreased Rab7a dephosphorylation and reduced Rab7a activity, thereby contributing to autophagosome accumulation. We further investigated the role of neuronal exosomes in the autophagy process. Our results demonstrated that the miRNA expression profiles in exosomes released by METH-induced SH-SY5Y cells were significantly altered, with 122 miRNAs upregulated and 151 miRNAs downregulated. KEGG and GO enrichment analyses of these differentially expressed miRNAs and their target genes revealed significant associations with the autophagy pathway and potential regulation of PTEN expression. Our experiments confirmed that METH-induced exosomes reduced PTEN expression levels and decreased Rab7a dephosphorylation, thereby exacerbating autophagic flux impairment and autophagosome accumulation. In conclusion, our study indicated that METH and its induced neuronal exosomes downregulate PTEN expression, leading to reduced Rab7a dephosphorylation. This, in turn, hinders the fusion of autophagosomes and lysosomes, ultimately resulting in autophagic flux impairment and neuronal damage.
Reactive oxygen species (ROS) are widely considered key to pathogenesis in chronic metabolic disease. Consequently, much attention is rightly focused on minimising oxidative damage. However, for ROS production to be most effectively modulated, it is crucial to first appreciate that ROS do not solely function as pathological mediators. There are >90 gene products specifically evolved to generate, handle, and tightly buffer the cellular concentration of ROS. Therefore, it is likely that ROS plays a role as integral homeostatic signalling components and only become toxic in extremis. This review explores these commonly overlooked normal physiological functions, including how ROS are generated in response to environmental or hormonal stimuli, the mechanisms by which the signals are propagated and regulated, and how the cell effectively brings the signal to an end after an appropriate duration. In the course of this, several specific and better-characterised signalling mechanisms that rely upon ROS are explored, and the threshold at which ROS cross from beneficial signalling molecules to pathology mediators is discussed.
Aucubin (AU) is one of the main components of the traditional Chinese medicine Eucommia ulmoides Oliv (EU). This study investigated the effects of AU on aging-related skeletal muscle atrophy in vitro and in vivo. The results of network pharmacology revealed the potential therapeutic effects of AU on muscle atrophy. In vitro, AU effectively attenuated D-gal-induced cellular damage, reduced the number of senescence-associated β-galactosidase (SA-β-Gal)-positive cells, down-regulated the expression levels of muscle atrophy-related proteins Atrogin-1 and MuRF1, and improved myotube differentiation, thereby mitigating myotube atrophy. Notably, AU was found to attenuate oxidative stress and apoptosis in skeletal muscle cells by reducing ROS production, regulating Cleaved caspase3 and BAX/Bcl-2 expression in apoptotic pathways, and enhancing Sirt1 and PGC-1α signaling pathways. In vivo studies demonstrated that AU treatment extended the average lifespan of Caenorhabditis elegans (C. elegans), increased locomotor activity, improved body wall muscle mitochondrial content, and alleviated oxidative damage in C. elegans. These findings suggested that AU can ameliorate aging-related muscle atrophy and show significant potential in preventing and treating muscle atrophy.
Porcine reproductive and respiratory syndrome (PRRS) is a pig respiratory disease threating the global swine industry. To combat PRRS, it is necessary of the effective diagnostic detection of antibody, including developing a neutralizing antibody against porcine reproductive and respiratory syndrome virus (PRRSV), especially the currently prevalent NADC30-like PRRSV in China. In this study, we prepared three monoclonal antibodies (mAbs) against NADC30-like PRRSV glycoprotein 5 (GP5) protein, and identified two corresponding precise epitopes (155WR156 and 196QWGRP200). In the neutralization test, 196QWGRP200 recognizing GP5 mAbs (11E6 and 12D1) exhibited obvious neutralizing activity, whereas the 155WR156 recognizing mAb (3A8) showed low neutralizing activity. Based on the two antigenic peptides, a peptide-based Enzyme-Linked Immunosorbent Assay (ELISA) was developed to detect antibodies against PRRSV, presenting high specificity, sensitivity, and repeatability. The concordance rate of the peptide-based ELISA and commercial IDEXX PRRSV X3 Ab ELISA in detection of 81 clinical samples was 82.7%. In conclusion, the GP5 peptide-based ELISA can be used for the detection of neutralizing antibodies against NADC30-like PRRSV, providing a rapid and reliable method for monitoring PRRSV infection.
The Rab family of small guanosine triphosphatases (GTPases) are nucleotide-dependent switches. Mutations in Rabs can result in human diseases. Rab7a and Rab7b transition from early endosomes to lysosomes and are presumed to function similarly. Most studies look at Rab7a, less on Rab7b, with the underlying assumption they function similarly. There have yet to be articles comparing them side by side. Whilst cloning Rab7 homologues, we identified splice isoforms for Rab7b only. These splice isoforms, Rab7b2 and Rab7bx8 lacking different exons, have not been previously characterized but suggest alternative function(s) for Rab7b. Thus, we hypothesize that Rab7 homologues have distinct functions. Here, we compare Rab7a and Rab7b nucleotide mutants locked in GDP-bound (Rab7T22N), GTP-bound (Rab7Q67L), nucleotide-free (Rab7aN125I/Rab7bN124I) states and characterized localization of the Rab7b splice isoforms. HeLa cells were transiently transfected with fluorescently tagged Rab7 reporters. Confocal images were processed with ImageJ and analyzed with SPSS. Rab7a and Rab7b nucleotide mutants were significantly different to one another. Approximately 50% of Rab7b splice isoform-expressing cells had aggregated vesicles, which were phenotypically different from Rab7b vesicles. Rab7a and Rab7b vesicles shared approximately 60% colocalization with each other, while Rab7b vesicles preferentially localized to the Trans Golgi Network. Our results suggest Rab7b is distinct from Rab7a, and Rab7b splice isoforms have different biological functions.
Chinese cabbage (Brassica rapa L. ssp. pekinensis) is a key vegetable crop in Asia, but its commercial value is often reduced by premature flowering triggered by vernalization. The molecular mechanisms behind this process are not fully understood. MADS-box genes, as crucial transcriptional regulators, play vital roles in plant development, including flowering. In this study, 102 MADS-box genes were identified in Chinese cabbage through bioinformatics analyses, covering phylogeny, chromosomal localization, and gene structure. Real-time quantitative PCR and RNA-seq data analysis revealed that the expression level of AGL27 declined as vernalization time increased. To determine BrAGL27′s functions, we obtained BrAGL27-overexpressed (OE) Arabidopsis thaliana lines that showed significantly later flowering compared with the wild type (WT). The expression levels of flowering suppressor genes AtFLC and AtTEM1 were significantly high-regulated in the BrAGL27-OE lines compared to WT plants, while the expression levels of the floral genes AtSPL15, AtSOC1, AtFT, and AtAP3 were significantly lower in the BrAGL27-overexpressed lines than in the wild type. These findings enhance understanding of MADS-box genes in vernalization and flowering regulation, offering a basis for further research on bolting resistance and flowering control in Chinese cabbage.
The endothelial layer, formed by endothelial cells, performs crucial functions in maintaining homeostasis. The endothelial integrity and function might be compromised due to various causes, including infection by Toxoplasma gondii, leading to an endothelial dysfunction. Toxoplasma gondii is an Apicomplexa parasite that infects a broad range of animals, including humans. This parasite can invade all nucleated cells, as well as endothelial cells. The interaction between this protozoan and endothelial cells can be mediated by different molecules, such as extracellular vesicles (EVs), which may either favor or hinder the infectious process. To investigate this interaction, we evaluated the infection of T. gondii on human brain microvascular endothelial cells (HBMEC) and human umbilical vein endothelial cells (HUVEC), in addition to assessing transcriptional changes. We also featured the EVs secreted by T. gondii and by infected and non-infected HBMEC and HUVEC. Finally, we evaluated the infection of cells stimulated with EVs of parasitic or cellular origin. Our results demonstrated that HUVEC not only exhibit a higher infection rate than HBMEC but also display a more pro-inflammatory transcriptional profile, with increased expression of interleukin-6 (IL6), interleukin-8 (IL8), and monocyte chemotactic protein-1 (MCP1) following infection. Additionally, we observed few differences in the concentration, distribution, and morphology of EVs secreted by both cell types, although their properties in modulating infection varied significantly. When cells were EVs stimulated, EVs from T. gondii promoted an increase in the HBMEC infection, EVs from infected or uninfected HBMEC reduced the infection, whereas EVs from HUVEC had no effect on the infectious process. In conclusion, our data indicate that T. gondii infection induces distinct changes in different endothelial cell types, and EVs from these cells can contribute to the resolution of the infection.
Background: CDK4/6 inhibitors (CDK4/6i) combined with hormone therapies have demonstrated clinical benefit in HR+, HER2- breast cancer patients. However, the onset of resistance remains a concern and highlights a need for therapeutic strategies to improve outcomes. The objective of this study was to develop an in vitro model to better understand the mechanisms of resistance to CDK4/6i + hormone therapies and identify therapeutic strategies with potential to overcome this resistance. Methods: The HR+, HER2− T47D breast cancer cell line genetically modified with a Geminin–Venus reporter construct was treated with CDK4/6i (abemaciclib or palbociclib) in combination with 4-hydroxytamoxifen (tamoxifen). Resistant cells were identified by cell sorting for Geminin (%GEM+), a marker of the S/G2/M phases of the cell cycle, and confirmed by treatment with tamoxifen plus the CDK4/6i used to drive resistance. In resistant cells, following treatment with CDK4/6i + ET (tamoxifen or fulvestrant), the effects on cell proliferation (%GEM+) and viability, gene expression, and protein analysis to evaluate CDK4/6–cyclin D complex composition were examined. Results: Palbociclib + tamoxifen-resistant (PTxR) cells treated with abemaciclib + ET showed decreased %GEM+, %Ki67, and colony formation ability, compared to abemaciclib + tamoxifen-resistant (ATxR) cells treated with palbociclib + ET. Additionally, PTxR cells showed increased CDK4-p21 interaction, compared to ATxR. The CDK6 levels were greater in ATxR cells compared to PTxR cells, associated with CDK4/6i resistance. Additionally, abemaciclib + fulvestrant continued to robustly decrease pRb levels in PTxR models compared to palbociclib + fulvestrant in ATxR models. Transcriptome analysis revealed a depression of the cell cycle and E2F- and Rb-related genes in PTxR cells following treatment with abemaciclib + ET, not present in ATxR cells treated with palbociclib + ET. Both resistant models showed increased EGFR-related gene expression. Conclusion: Taken together, we describe CDK4/6i-dependent mechanisms resulting in early-onset resistance to CDK4/6i + ET, using clinically relevant drug concentrations, in preclinical breast cancer cell models. The characterization of these preclinical models post progression on CDK4/6 inhibitor + ET treatment highlights the potential that the specific sequencing of CDK4/6 inhibitors could offer to overcome acquired resistance to CDK4/6i + ET. Abemaciclib + fulvestrant is currently under clinical investigation in patients with HR+, HER2− breast cancer and progression on prior CDK4/6i + ET (NCT05169567, postMONARCH).
Ocular aqueous humor plays an important role in maintaining retinal function. Recent findings indicate that aqueous humor, which flows into the vitreous body, is probably absorbed by Müller cells in the retina, and this process is mediated by aquaporin-4. In this review, we aim to summarize the results of studies on classical aqueous humor circulation and postiridial flow, a pathway proposed in the late 1980s for the inflow of aqueous humor into the vitreous body. In addition, we aim to discuss the retinal glymphatic pathway, inferred by recent findings, with a focus on the anatomical location of aquaporins and barriers that regulate water movement within the tissue. Similarly to the cerebral glymphatic flow, the function of the retinal glymphatic pathway may decline with age, as supported by our findings. In this review, we also discuss age-related ocular diseases that might be associated with the dysfunction of the retinal glymphatic pathway.
Salinity is a major environmental factor that adversely affects plant growth and production. Cuticular wax protects plants against external environmental stress. The relationship between cuticular wax biosynthesis and salt tolerance remains unclear in Salicornia europaea. This study examined the cuticle thickness, wax load, morphology, composition, and the expression of cuticular wax biosynthesis gene identification and expression. The results showed that 600 mM NaCl treatment enhanced the cuticle thickness and total wax load; crystal wax structures were also observed after NaCl treatment. The cuticular wax was mainly composed of fatty acids, alcohols, alkenes, and esters. The alcohol class accounted for the largest proportion, with docosanol (C25H54OSi) being the main specific alcohol compound, followed by fatty acids and alkanes. After a sequence database search, six fatty acyl-CoA reductases (FARs), sixteen wax synthase/diacylglycerol acyltransferases (WS/DGATs), three fatty alcohol oxidases (FAOs), five eceriferums (CERs), and eight mid-chain alkanes (MAHs) were identified as the putative wax biosynthesis enzymes. Their expression analysis revealed a differential response to 100 and 600 mM NaCl treatment and reached the highest level at 12 h or 48 h. The genes that were evidently upregulated with higher fold changes under salinity, such as SeFAR1, SeFAR2, and SeFAR3 are implied to synthesize primary alcohols, and SeWSs convert the primary alcohols to wax esters; SeCER1 and SeCER3 are also supposed to catalyze the conversion of aldehydes to alkanes while SeMAH7 catalyze alkanes to secondary alcohols in S. europaea in response to NaCl treatment. This study demonstrated that both the decarbonylation and acyl-reduction wax biosynthesis pathways may not be independent from each other.
Cervical cancer is the fourth leading cause of cancer mortality in women worldwide, with limited therapeutic options for advanced or recurrent cases. In this study, the effects of a recent thieno[2,3-b]pyridine derivative, (E)-3-amino-5-(3-bromophenyl)acryloyl)-N-(3-chloro-2-methylphenyl)-6-methylthieno[2,3-b]pyridine-2-carboxamide (compound 1), on two cervical cancer cell lines, HeLa and SiHa, are investigated. Cytotoxicity was assessed by MTT assay, apoptosis rates were measured by flow cytometry, and metabolic profiling was performed by GC-MS. The study also examined the expression of eight glycosphingolipids (GSLs) in cancer stem cells (CSCs) and non-CSCs to assess glycophenotypic changes. Compound 1 showed significant cytotoxicity in both cell lines, with apoptosis identified as the primary mechanism of cell death. A significant reduction in the CSC population was observed, particularly in the SiHa cell line. Compound 1 treatment altered GSL expression and decreased GM2 levels in both CSCs and non-CSCs in the SiHa cell line and Gg3Cer levels in the HeLa cell line. Metabolic profiling identified 23 and 21 metabolites in the HeLa and SiHa cell lines, respectively, with significant differences in metabolite expression after treatment. These results underscore the potential of compound 1 as a promising therapeutic candidate for cervical cancer and warrant further investigation in preclinical and clinical settings.
Meat production traits in pigs are critical economic characteristics, primarily influenced by the formation and development of skeletal muscle. Skeletal muscle development is regulated by a complex transcriptional network, which partly relies on chromatin accessibility for initiation. Ningxiang pigs, a renowned Chinese indigenous breed, are highly valued for their tender meat. However, studies focusing on skeletal muscle development in Ningxiang pigs, particularly from the perspective of chromatin accessibility, have not yet been reported. Based on this, the present study selected several key time points in the skeletal muscle development of Ningxiang pigs to perform Transposase-Accessible Chromatin Sequencing (ATAC-seq) and RNA sequencing (RNA-seq). This was carried out to identify key open chromatin regions and genes during different growth stages, which could influence skeletal muscle development in Ningxiang pigs. We collected longissimus dorsi muscle samples at postnatal days 14 (D14), 28 (D28), 85 (D85), 165 (D165), and 250 (D250). For each age, three individuals were collected for ATAC-seq and RNA-seq. After initial differential analysis among different ages, we identified 6412 differentially accessible chromatin peaks and 1464 differentially expressed genes. To clarify the key candidate transcription factors affecting the development of skeletal muscle in Ningxiang pigs, motif analysis of differential peaks revealed potential cis-regulatory elements with binding sites for transcription factors, including Fosl2 and JunB. Correlation analysis identified 56 overlapping genes and a significant positive correlation (r = 0.73, p = 1 × 10−14) between gene expression and chromatin accessibility. Key candidate genes such as HOXA10, closely related to skeletal muscle development, were specifically examined. These results enhance our understanding of the genetic and epigenetic regulatory mechanisms of porcine skeletal muscle development, providing a robust foundation for future molecular studies.
We aimed to determine whether transient global amnesia (TGA) is associated with alterations in central nervous system (CNS) injury biomarkers—serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP). In a prospective cohort of TGA patients, blood samples were obtained within 24–48 h of TGA onset (t0) and 6 weeks thereafter (t1). We assessed sNfL and sGFAP levels using the highly sensitive single-molecule array assay and calculated Z-scores adjusted for age, gender, and body mass index (BMI). Demographics, electroencephalography (EEG), and cerebral magnetic resonance imaging (cMRI) findings were also collected. A total of 20 patients were included (median age: 66 years, 70% women). No significant changes in sNfL or sGFAP levels associated with TGA at t0 and t1 were observed. Median sNfL Z-scores were 0.45 (interquartile range [IQR] −0.09, 1.19) at t0 and 0.60 (IQR −0.61, 1.19) at t1. Median sGFAP Z-scores were 0.27 (IQR −0.45, 0.76) at t0 and 0.44 (IQR −0.27, 0.75) at t1. Similarly, in the subgroup of patients with diffusion-weighted imaging (DWI)-positive hippocampal lesions (n = 5/20[25%]), no elevations in blood biomarkers were detected. Our pilot study on neurological blood biomarkers supports the benign nature of TGA, indicating that no CNS tissue damage occurs.
Arabinogalactan proteins (AGPs) are complex proteoglycans present in plant cell walls across the kingdom. They play crucial roles in biological functions throughout the plant life cycle. In this study, we identified 43 gene members of the AG peptide (an AGP subfamily) within the rice genome, detailing their structure, protein-conserved domains, and motif compositions for the first time. We also examined the expression patterns of these genes across 18 tissues and organs, especially the different parts of the flower (anthers, pollen, pistil, sperm cells, and egg cells). Interestingly, the expression of some AG peptides is mainly present in the pollen grain. Transcription data and GUS staining confirmed that OsAGP6P—a member of the AG peptide gene family—is expressed in the stamen during pollen development stages 11–14, which are critical for maturation as microspores form after meiosis of pollen mother cells. It became noticeable from stage 11, when exine formation occurred—specifically at stage 12, when the intine began to develop. The overexpression of this gene in rice decreased the seed-setting rate (from 91.5% to 30.5%) and plant height (by 21.9%) but increased the tillering number (by 34.1%). These results indicate that AGP6P contributes to the development and fertility of pollen, making it a valuable gene target for future genetic manipulation of plant sterility through gene overexpression or editing.
To investigate levels of specific plasma-biomarkers related to neurodegeneration and inflammation in patients with different chronic degenerative retinal diseases, using an ultrasensitive technology called ‘single molecule array’ (SiMoA). Also, to investigate if biomarkers were measurable in the patient’s blood, dependent on age and medical comorbidities, and useful for stratifying the diseases. This exploratory, cross-sectional study recruited 151 adults at the Department of Ophthalmology, Rigshospitalet, Denmark (period 2019 to 2020). Clinical data came from the electronic medical-record system. The study population consisted of 131 patients: 32 with diabetic retinopathy (DR; 51 diabetes, DM), 27 with glaucoma, 53 with inherited retinal degeneration (IRD and 20 healthy controls (HC). Medical comorbidities included organ failure, other active eye diseases, and comorbidities. Three biomarkers, neurofilament-light-chain (NFL), glial-fibrillary-acidic-protein (GFAP), and CXC-motif chemokine ligand 13 (CXCL13), were measured with SiMoA technology. The age-adjusted values were reported as fold differences (FD) with 95% confidence intervals (CI). Increased NFL levels were found in DR patients compared to HCs (FD 1.81 95%CI 1.43, 2.28, p < 0.001, adj-p < 0.001). Similarly increased NFL levels were reported in advanced DR (PDR, DME), compared to both DM (FD 2.52 (95%CI: 1.71; 3.72, p < 0.001, adj-p < 0.001, and FD 2.04 (95%CI: 1.33; 3.12, p < 0.001, adj-p < 0.001), respectively) and HCs (FD 2.35 (95%CI: 1.67; 3.30, p < 0.001, adj-p < 0.001), and FD 1.89 (95%CI: 1.28; 2.79, p < 0.001, adj-p < 0.001) respectively). Independent of comorbidities, decreased NFL-levels were seen in IRD compared to DR (FD 0.49 (95% CI 0.39; 0.61, p < 0.001; adj-p < 0.001), ±comorbidities). Decreased GFAP levels were seen in DM patients compared to HCs (FD 0.69; 95%CI 0.55, 0.87, p = 0.002, adj-p = 0.02), but contrary to an increasing trend in advanced DR compared to DM (-comorbidities). These results imply that these biomarker-tests are useful for detecting and monitoring development of retinopathy in the circulations of diabetes patients. Plasma-biomarkers may be useful to stratify between retinal disease types. Prospective studies are underway to explore this hypothesis in depth.
Animal embryos are vital tools in scientific research, providing insights into biological processes and disease mechanisms. This paper explores their historical and contemporary significance, highlighting the shift towards the refinement of in vitro systems as alternatives to animal experimentation. We have conducted a data review of the relevant literature on the use of embryos in research and synthesized the data to highlight the importance of this model for scientific progress and the ethical considerations and regulations surrounding embryo research, emphasizing the importance of minimizing animal suffering while promoting scientific progress through the principles of replacement, reduction, and refinement. Embryos from a wide range of species, including mammals, fish, birds, amphibians, and reptiles, play a crucial experimental role in enabling us to understand factors such as substance toxicity, embryonic development, metabolic pathways, physiological processes, etc., that contribute to the advancement of the biological sciences. To apply this model effectively, it is essential to match the research objectives with the most appropriate methodology, ensuring that the chosen approach is appropriate for the scope of the study.
This article investigated the composition and content of volatile organic compounds (VOCs) in cumin from three Xinjiang origins (Hami, Turpan, and Hetian) at different processing temperatures. VOCs varied with temperature and origin, but alcohols and terpenes were predominant in all samples. Hetian cumin exhibited the highest VOC content and stability under specific treatments, divided into an ambient temperature treatment (AMB) and a 70 °C heat treatment. A cluster analysis revealed high similarity between replicates and significant differences among the samples. A Venn diagram comparison showed that 70 °C processing reduced the number of common VOCs among the three origins from 36 to 19, which is a decrease of 47.22%, indicating a significant impact of heating on cumin VOCs and possibly promoting the formation of new compounds. Finally, utilizing the varying abilities of different types of polyphenols to inhibit heterocyclic aromatic amines (HAAs), six polyphenolic compounds, identified as sesamin, 6-caffeoylsucrose, apigenin, eschweilenol C, kaempferol glucuronide, and luteolin, were preliminarily determined to play an active role in the β-carboline HAA simulation system.
Antlers, as the only fully regenerable bone tissue in mammals, serve as an exceptional model for investigating bone growth, mineralization, articular cartilage repair, and the pathophysiology of osteoporosis. Nevertheless, the exact molecular mechanisms governing osteogenesis, particularly the dynamic cellular interactions and signaling pathways coordinating these processes, remain poorly characterized. This study used single-cell RNA sequencing (scRNA-seq) on the 10× Genomics Chromium platform, combined with bulk-RNA sequencing results, to comprehensively analyze molecular regulatory mechanisms in rapid antler osteogenesis. The results showed that eight cell types were identified in sika deer antler during the growth and ossification stages: mesenchymal, chondrocyte, osteoblast, pericyte, endothelial, monocyte/macrophage, osteoclast, and NK cells. Chondrocytes were predominantly found during the growth stage, while osteoblasts were more abundant during the ossification stage. Mesenchymal cells were subclassified into three subcategories: MSC_1 (VCAN and SFRP2), MSC_2 (TOP2A, MKI67), and MSC_3 (LYVE1 and TNN). MSC_3 was predominantly present during the growth stage. During the growth stage, MSC_1 and MSC_2 upregulated genes related to vasculature development (COL8A1, NRP1) and cell differentiation (PTN, SFRP2). During the ossification stage, these subcategories upregulated genes involved in the positive regulation of p53 class mediator signal transduction (RPL37, RPL23, RPS20, and RPL26), osteoblast differentiation (SPP1, IBSP, BGLAP), and proton-motive ATP synthesis (NDUFA7, NDUFB3, NDUFA3, NDUFB1). Endothelial cells were categorized into five subpopulations: Enc_1 (SPARCL1, VWF), Enc_2 (MCM5), Enc_3 (ASPM, MKI67), Enc_4 (SAT1, CXCL12), and Enc_5 (ZFHX4, COL6A3). Combined scRNA-seq and bulk RNA-seq analysis revealed that the ossification stage’s upregulation genes included osteoclast- and endothelial cell-specific genes, while the growth stage’s upregulation genes were mainly linked to collagen organization, osteoblast differentiation, mitotic cell cycle, and chondrocyte differentiation. Overall, this study offers a detailed single-cell analysis of gene expression patterns in antlers during the growth and ossification stages, providing insights into the molecular mechanisms driving rapid osteogenesis.
Heart failure (HF) remains a major cause of mortality worldwide. While novel approaches, including gene and cell therapies, show promise, efficient delivery methods for such biologics to the heart are critically needed. One emerging strategy is lung-to-heart delivery using nanoparticle (NP)-encapsulated biologics. This study examines the efficiency of delivering a therapeutic peptide conjugated to a cell-penetrating peptide (CPP) to the heart via the lung-to-heart route through intratracheal (IT) injection in mice. The CPP, a tandem repeat of NP2 (dNP2) derived from the human novel LZAP-binding protein (NLBP), facilitates intracellular delivery of the therapeutic payload. The therapeutic peptide, SE, is a decoy peptide designed to inhibit protein phosphatase 1 (PP1)-mediated dephosphorylation of phospholamban (PLN). Our results demonstrated that IT injection of dNP2-SE facilitated efficient delivery to the heart, with peak accumulation at 3 h post-injection. The administration of dNP2-SE significantly ameliorated morphological and functional deterioration of the heart under myocardial infarction. At the molecular level, dNP2-SE effectively prevented PLN dephosphorylation in the heart. Immunoprecipitation experiments further revealed that dNP2-SE binds strongly to PP1 and disrupts its interaction with PLN. Collectively, our findings suggest that lung-to-heart delivery of a CPP-conjugated therapeutic peptide, dNP2-SE, represents a promising approach for the treatment of HF.
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AbstractMutations in the cyclin-dependent kinase-like 5 gene (CDKL5) cause a severe neurodevelopmental disorder, yet the impact of truncating mutations remains unclear. Here, we introduce theCdkl5492stopmouse model, mimicking C-terminal truncating mutations in patients. 492stop/Y mice exhibit altered dendritic spine morphology and spontaneous seizure-like behaviors, alongside other behavioral deficits. After creating cell lines with variousCdkl5truncating mutations, we found that these mutations are regulated by the nonsense-mediated RNA decay pathway. Most truncating mutations result in CDKL5 protein loss, leading to multiple disease phenotypes, and offering new insights into the pathogenesis of CDKL5 disorder.
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AbstractEpilepsy affects over 50 million people worldwide. Drug-resistant epilepsy (DRE) accounts for up to a third of these cases, and neuro-inflammation is thought to play a role in such cases. Despite being a long-debated issue in the field of DRE, the mechanisms underlying neuroinflammation have yet to be fully elucidated. The pro-inflammatory microenvironment within the brain tissue of people with DRE has been probed using single-cell multimodal transcriptomics. Evidence suggests that inflammatory cells and pro-inflammatory cytokines in the nervous system can lead to extensive biochemical changes, such as connexin hemichannel excitability and disruption of neurotransmitter homeostasis. The presence of inflammation may give rise to neuronal network abnormalities that suppress endogenous antiepileptic systems. We focus on the role of neuroinflammation and brain network anomalies in DRE from multiple perspectives to identify critical points for clinical application. We hope to provide an insightful overview to advance the quest for better DRE treatments.
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AbstractAccurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified ade novoheterozygous mutation inTMEM63A(c.1894G>A; p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca2+influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generatedTmem63aknockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures ofTmem63a−/−OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation ofTmem63a−/−OPCsin vitroand myelination inTmem63a−/−mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca2+influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.
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AbstractSocial Anxiety Disorder (SAD) involves fear of negative evaluation and social avoidance, impacting quality of life. Early life adversities (ELA) are recognized as risk factors for SAD. Previous research indicated inconsistent alterations in resting state functional connectivity (RSFC) in SAD, particularly in the prefrontal cortex and precuneus. This study investigated the interaction between SAD and ELA at the RSFC level. Functional magnetic resonance imaging (fMRI) was conducted on 120 participants (aged 19–48). Four groups were formed: low/ high ELA controls (n = 49, n = 22) and low/ high ELA SAD participants (n = 30, n = 19). Seed-based correlation analyses (SCA) and multi-voxel pattern analysis (MVPA) were applied. A network in which ELA moderates the neural correlates of SAD during the resting state was identified, involving key nodes like the subgenual anterior cingulate cortex, left middle frontal gyrus, and an area in the calcarine fissure/precuneus. Five distinct interaction patterns of SAD and ELA were observed, showcasing opposite RSFC patterns in individuals with SAD based on ELA experience. Results remained significant when controlled for general anxiety and depression measures. Emotional aspects of ELA played a significant role in these interactions. These findings stress the necessity of considering primarily emotional ELA as covariate in neuroimaging studies investigating SAD and potentially also other psychiatric disorders, addressing inconsistencies in prior research. The left middle frontal gyrus emerges as a link in the SAD-ELA interaction during resting state and anxiety-relevant stimulation. Longitudinal studies, starting from childhood, are needed to understand ELA’s impact on brain function and to identify potential neuromarkers for SAD predisposition post-ELA exposure.
AbstractAge-related alterations in GABAergic function, including depletion of cortical GABA concentrations, is likely associated with declining cognitive performance in normative aging. However, the extent to which GABAergic function is perturbed in the highest-functioning stratum of the oldest-old (85+) population is unknown. For the first time, we report the stability of cortical GABA in this population. We extend our previously-reported Individual Participant Data Meta-Analysis of GABA levels across the lifespan, integrating four large cross-sectional datasets sampling cognitively-intact oldest-old adults. Within our lifespan model, the slope of age-related GABA differences in cognitively-intact oldest-old adults flattens after roughly age 80; within oldest-old adults only, inclusion of age does not improve the fit of models predicting GABA. We interpret these findings as an effect of survivorship: inclusion in the study required intact cognition, and too great a reduction of GABA levels may not be compatible with neurophysiological function needed for intact cognition. This work contributes to a growing body of evidence suggesting that successful cognitive aging may require intact GABAergic function, as well as further characterizing successful aging amongst oldest-old adults and emphasizing GABA as a potential target for interventions to prolong cognitive health in aging.
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AbstractSensory symptoms are highly prevalent amongst autistic individuals and are now considered in the diagnostic criteria. Whilst evidence suggests a genetic relationship between autism and sensory symptoms, sensory symptoms are neither universal within autism nor unique to autism. One explanation for the heterogeneity within autism and commonality across conditions with respect to sensory symptoms, is that it is alexithymia (a condition associated with difficulties identifying and describing one’s own emotions) that has a genetic relationship with sensory symptoms, and that alexithymia commonly co-occurs with autism and with several other conditions. Using parent-reports of symptoms in a sample of adolescent twins, we sought to examine the genetic association between autism, alexithymia and sensory symptoms. Results showed that the genetic correlation between autism and sensory symptoms was not significant after controlling for alexithymia. In contrast, after controlling for variance in alexithymia explained by autism, the genetic correlation between alexithymia and sensory symptoms was significant (and the proportion of variance explained by genetic factors remained consistent after controlling for autism). These results suggest that 1) alexithymia and sensory symptoms share aetiology that is not accounted for by their association with autism and 2) that the genetic association between sensory symptoms and autism may be, in part or wholly, a product of alexithymia. Future research should seek to examine the contribution of alexithymia to sensory symptoms across other conditions.
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AbstractStudies have shown gamma-amino-butyric acid (GABA) and Glx (a combination of glutamate and glutamine) to be altered in major depressive disorder (MDD). Using proton Magnetic Resonance Spectroscopy (1H-MRS), this study aimed to determine whether lower pretreatment GABA and Glx levels in the medial frontal cortex, a region implicated in MDD pathophysiology, are associated with better antidepressant treatment response. Participants with MDD (N= 74) were antidepressant naïve or medication-free for at least three weeks before imaging. Two MEGA-PRESS1H-MRS acquisitions were collected, interleaved with a water unsuppressed reference scan. GABA and Glx concentrations were quantified from an average difference spectrum, with preprocessing using Gannet and spectral fitting using TARQUIN. Following imaging, participants were randomized to escitalopram or placebo for 8 weeks in a double-blind design. Multivariable logistic regression models were applied with treatment type and age as covariates. Bayes Factor hypothesis testing was used to interpret the strength of the evidence. No significant association was found between pretreatment Glx, GABA, or Glx/GABA and depression remission status or the continuous outcome, percent change in symptom severity. In an exploratory analysis, no significant correlation was found between pretreatment Glx, GABA or Glx/GABA and days to response. Bayes factor analysis showed strong evidence towards the null hypotheses in all cases. To date, there are no replicated biomarkers in psychiatry. To address this, well-powered, placebo-controlled trials need to be undertaken and reported. The present analysis suggests pretreatment GABA, Glx, or their ratio cannot predict antidepressant treatment response. Future direction including examining glutamate and glutamine separately or examining biological subtypes of MDD separately.Trial Name: Advancing Personalized Antidepressant Treatment Using PET/MRI.Registration Number: NCT02623205 URL:https://clinicaltrials.gov/ct2/show/NCT02623205
AbstractLoss of glutamatergic terminals is hypothesised to contribute to excitation-inhibition imbalance in schizophrenia, supported by evidence that the normal positive association between glutamate concentrations and synaptic terminal density is not found in patients with chronic schizophrenia. However, it is unknown whether the relationship between synaptic terminal density and glutamate levels is altered early in the course of illness. To address this, we investigated [11C]UCB-J distribution volume ratio (DVR) and glutamatergic markers in healthy volunteers (HV) and in antipsychotic-naïve/free patients with schizophrenia (SCZ) recruited from first-episode psychosis services. Forty volunteers (HVn= 19, SCZn= 21) underwent [11C]UCB-J positron emission tomography and proton magnetic resonance spectroscopy (1H-MRS) imaging in the anterior cingulate cortex (ACC) and left hippocampus to index [11C]UCB-J DVR and creatine-scaled glutamate (Glu/Cr) and glutamate in combination with glutamine (Glx/Cr). In the HV but not SCZ group, [11C]UCB-J DVR was significantly positively associated with Glu/Cr (Spearman’s rho = 0.55,p= 0.02) and Glx/Cr (Spearman’s rho = 0.73,p= 0.0004) in the ACC, and with Glu/Cr in the left hippocampus (Spearman’s rho = 0.77,p= 0.0001). DVR was significantly lower in the ACC in the SCZ group compared to the HV group (Kolmogorov-Smirnov Z = 1.44,p= 0.03). Together, these findings indicate that the normal relationship between levels of a synaptic terminal density marker and levels of glutamate is disrupted early in the course of schizophrenia. This is consistent with the hypothesis that there is loss of glutamatergic terminals at illness onset.
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AbstractWithin precision psychiatry, there is a growing interest in normative models given their ability to parse heterogeneity. While they are intuitive and informative, the technical expertise and resources required to develop normative models may not be accessible to most researchers. Here we present Neurofind, a new freely available tool that bridges this gap by wrapping sound and previously tested methods on data harmonisation and advanced normative models into a web-based platform that requires minimal input from the user. We explain how Neurofind was developed, how to use the Neurofind website in four simple steps (www.neurofind.ai), and provide exemplar applications. Neurofind takes as input structural MRI images and outputs two main metrics derived from independent normative models: (1) Outlier Index Score, a deviation score from the normative brain morphology, and (2) Brain Age, the predicted age based on an individual’s brain morphometry. The tool was trained on 3362 images of healthy controls aged 20–80 from publicly available datasets. The volume of 101 cortical and subcortical regions was extracted and modelled with an adversarial autoencoder for the Outlier index model and a support vector regression for the Brain age model. To illustrate potential applications, we applied Neurofind to 364 images from three independent datasets of patients diagnosed with Alzheimer’s disease and schizophrenia. In Alzheimer’s disease, 55.2% of patients had very extreme Outlier Index Scores, mostly driven by larger deviations in temporal-limbic structures and ventricles. Patients were also homogeneous in how they deviated from the norm. Conversely, only 30.1% of schizophrenia patients were extreme outliers, due to deviations in the hippocampus and pallidum, and patients tended to be more heterogeneous than controls. Both groups showed signs of accelerated brain ageing.
AbstractObsessive-compulsive disorder (OCD), a disabling and notoriously treatment-resistant neuropsychiatric disorder, affects 2–3% of the general population and is characterized by recurring, intrusive thoughts (obsessions) and repetitive, ritualistic behaviors (compulsions). Although long associated with dysfunction within the cortico-striato-thalamic-cortical circuits, the thalamic role in OCD pathogenesis remains highly understudied in the literature. Here, we identified a rat thalamic nucleus – the reuniens (NRe) – that mediates persistent, compulsive self-grooming behavior. Optogenetic activation of this nucleus triggers immediate, excessive grooming with strong irresistibility, increases anxiety, and induces negative affective valence. A thalamic-hypothalamic pathway linking NRe to the dorsal premammillary nucleus (PMd) was discovered to mediate excessive self-grooming behavior and render it a defensive coping response to stress, mirroring the compulsions faced by OCD patients. Given the close resemblance between this self-grooming behavior and the clinical manifestations of OCD, the results from this study highlight the role of NRe in mediating OCD-like compulsive behaviors. This can be attributed to NRe’s position at the nexus of an extensive frontal-striatal-thalamic network regulating cognition, emotion, and stress-related behaviors, suggesting NRe as a potential novel target for intervention.
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AbstractAcylcarnitines (ACs) are involved in bioenergetics processes that may play a role in the pathophysiology of depression. Previous genomic evidence identified four ACs potentially linked to depression risk. We carried forward these ACs and tested the association of their circulating levels with Major Depressive Disorder (MDD) diagnosis, overall depression severity and specific symptom profiles. The sample from the Netherlands Study of Depression and Anxiety included participants with current (n = 1035) or remitted (n = 739) MDD and healthy controls (n = 800). Plasma levels of four ACs (short-chain: acetylcarnitine C2 and propionylcarnitine C3; medium-chain: octanoylcarnitine C8 and decanoylcarnitine C10) were measured. Overall depression severity as well as atypical/energy-related (AES), anhedonic and melancholic symptom profiles were derived from the Inventory of Depressive Symptomatology. As compared to healthy controls, subjects with current or remitted MDD presented similarly lower mean C2 levels (Cohen’s d = 0.2, p ≤ 1e-4). Higher overall depression severity was significantly associated with higher C3 levels (ß = 0.06, SE = 0.02, p = 1.21e-3). No associations were found for C8 and C10. Focusing on symptom profiles, only higher AES scores were linked to lower C2 (ß = −0.05, SE = 0.02, p = 1.85e-2) and higher C3 (ß = 0.08, SE = 0.02, p = 3.41e-5) levels. Results were confirmed in analyses pooling data with an additional internal replication sample from the same subjects measured at 6-year follow-up (totaling 4141 observations). Small alterations in levels of short-chain acylcarnitine levels were related to the presence and severity of depression, especially for symptoms reflecting altered energy homeostasis. Cellular metabolic dysfunctions may represent a key pathway in depression pathophysiology potentially accessible through AC metabolism.
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AbstractAnorexia nervosa (AN) typically emerges around adolescence and predominantly affects females. Recent progress has been made in identifying biological correlates of AN, but more research is needed to pinpoint the specific mechanisms that lead to its development and maintenance. There is a known phenotypic link between AN, growth and sexual maturation, yet the genetic overlap between these phenotypes remains enigmatic. One may hypothesize that shared factors between AN, energy metabolism and reproductive functions may have been under recent evolutionary selection. Here, we characterize the genetic overlap between AN, BMI and age at menarche, and aimed to reveal recent evolutionary factors that may help explain the origin of AN. We obtained publicly available GWAS summary statistics of AN, BMI and age at menarche and studied the polygenic overlap between them. Next, we used Neandertal Selective Sweep scores to explore recent evolutionary selection. We found 22 loci overlapping between AN and BMI, and 9 loci between AN and age at menarche, with 7 of these not previously associated with AN. We found that loci associated with AN may have been under particular evolutionary dynamic. Chronobiology appeared relevant to the studied genetic overlaps and prone to recent evolutionary selection, offering a promising avenue for future research. Taken together, our findings contribute to the understanding of the genetic underpinning of AN. Ultimately, better knowledge of the biological origins of AN may help to target specific biological processes and facilitate early intervention in individuals who are most at risk.
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AbstractThe blood–brain barrier (BBB) is essential for central nervous system (CNS) homeostasis by regulating permeability between the bloodstream and brain. This study evaluates the immortalized human brain capillary endothelial cell lines hCMEC/D3 and hBMEC for their use as a brain endothelial cells to investigate the OATP2B1 transporter following adenoviral infection. We assessed the impact of adenoviral-mediated OATP2B1 expression on BBB marker proteins and transporters using targeted and untargeted mass spectrometry-based proteomics. Targeted proteomics identified measurable levels of endothelial markers PECAM1 and CDH5 in hCMEC/D3, whereas these markers were undetectable in hBMEC. Both cell lines exhibited similar Pgp levels, while BCRP was absent in hCMEC/D3. The expression of uptake transporters was also evaluated, revealing comparable levels of GLUT1, ENT1, MCT1 and OAT7 in hCMEC/D3 and hBMEC. Although OATP2B1 levels did not significantly increase post-infection in targeted proteomics, untargeted proteomics confirmed enhanced OATP2B1 expression. Other BBB markers and transporters remained unaffected in both cell lines. Notably, hCMEC/D3 demonstrated a stronger BBB phenotype, indicated by higher expression of BBB markers and transporters, while adenoviral infection was more effective in hBMEC. The differences between targeted and untargeted proteomics underscore the need for diverse methods to verify protein expression levels. This comparative analysis provides insights into the strengths and limitations of hCMEC/D3 and hBMEC for BBB research, particularly regarding drug transport mechanisms.
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AbstractIn a healthy brain, neuroinflammation, controlled by the main intermediary for the immune response microglia and astrocytes, contributes to maintain physiological functions such as secretion of neurotrophic factors, removal of cell tau and amyloid-β (Aβ) debris, and local homeostasis. When the immune response becomes chronic, it can become pathological and fuel neuroinflammation, causing glial cells to malfunction and not perform their function of clearing debris, resulting in further damage to neurons. Multiple studies highlight that an intense crosstalk is activated between peripheral blood white cells (PBWCs) and central nervous system (CNS). Nevertheless, how PBWC can be carriers of biomarkers of the CNS neuropathological states it is still far to be completely known. In this work, we aimed to observe how PBWC content could be related to moderate-severity of DAT in order to have early signals from of pathological neurodegeneration brain initiate. Protein analysis have been performed in PBWC of Mild Cognitive Impairment (MCI) and DAT patients in respect to those of healthy controls and differently expressed proteins have been investigated. Our data showed a deregulation of pathways involved in neurodegeneration since from MCI level and deregulated proteins that can be considered markers for DAT onset and progression.
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AbstractThe transcription factor NUclear Receptor Related 1 (NURR1) regulates the development and maintenance of midbrain dopaminergic (mDA) neurons, which control voluntary movement, motivation, and reward. NURR1 also plays anti-inflammatory functions in microglia, protecting mDA neurons from inflammation-induced death. It remains to be determined to what extent NURR1 exerts its function in microglia. Interestingly, altered microglial phenotypes are associated to psychiatric conditions. NURR1 defects in male mice are associated with hyperactive and impulsive behaviour. Notably, such behaviour is accompanied by a normal development of mDA neurons which, at least in their number, are preserved. This study aims to explain the altered behaviour of NURR1-deficient mice by analyzing microglial compartment and inflammatory machinery that could be consistently altered to influence such observed behaviours. The present work demonstrates that NURR1 deficiency determines a reduction in the number of microglial cells specifically in the substantia nigra (SN), without altering their morphological activation state. Gene expression levels of molecules associated with active/protective microglial phenotype in the SN of NURR1+/−mice are altered. The level of HMOX, a marker of cellular damage/apoptosis, is up-regulated, while the level of MT2, a marker of response to stress, is reduced in the SN of NURR1+/−mice. The level of prostaglandin receptors, which are endogenous ligands for NURR1, is up-regulated in the same compartment. Overall, the NURR1-deficient mice, which exhibit impaired behaviour, have a reduced number of microglia cells and alterations of the inflammatory machinery in their SN.
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AbstractEarly life stress (ELS) is considered a risk factor for the development of cognitive and executive dysfunctions throughout development. The medial portion of the prefrontal cortex (mPFC) is directly implicated in short-term working memory. Furthermore, due to its late development compared to other brain regions, the mPFC is considered a vulnerable brain region to ELS exposure. Here, we investigated the effects of the ELS on PFC-dependent memory and mPFC transcriptomic profiles. From postnatal day (PND) 2 to PND 15, BALB/cJ mice were exposed to maternal separation (MS) for 3 h per day combined with limited bedding (ELS group) or left undisturbed (CT group). During the period of stress, maternal behavior was recorded pre-MS and post-MS. From PND 45 to PND 47, males and females were tested for working memory performance in the Y-maze and short-term recognition memory in the object in place task (OIP). Later, we assessed mRNA level alterations in the mPFC by RNA-seq. Here, we showed that ELS increases maternal care post-MS and the number of nest exits pre-MS and post-MS. Furthermore, males and females exposed to ELS exhibited impairments in the OIP, while only females performed worse in the Y-maze. With respect to the mPFC transcriptome, we identified 13 DEGs in the females, which were significantly influenced by chaperone-mediated protein folding processes, while 4 genes were altered in males. In conclusion, we showed that, compared with male sex, ELS alters maternal behavior and leads to more extensive impairments in memory function and transcriptomic alterations in females.
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Abstractβ‐3 adrenoceptor (AR) counteracts the β‐1 and β‐2 ARs and rescues the effects of excessive catecholamines. To test the hypothesis that a β‐3 AR agonist (mirabegron) can reverse the effects of isoproterenol (ISO) on ventricular fibrillation (VF), we performed optical mapping studies in six male and six female Langendorff perfused rabbit hearts at baseline and after sequential administration of ISO (100 nm), mirabegron (1000 nm), apamin (100 nm) and washout (Study I). An additional six male and six female hearts were studied with mirabegron doses ranging between 250 and 1000 nmwithout ISO (Study II). Patch clamp studies in human embryonic kidney 293 cells were performed to determine the effect of mirabegron on the apamin‐sensitive small conductance Ca2+activated K+current (IKAS). Study I show that ISO increased phase singularities per VF episode (PSs/VF) in females and the dominant frequency (DF) in both sexes. Mirabegron significantly decreased PSs/VF in both sexes and significantly decreased DF in females. Study II showed no significant difference in PSs/VF between sexes at mirabegron concentrations of 250 nmand 500 nm. However, females showed significantly lower PSs/VF than males at mirabegron concentrations of 750 nmand 1000 nm. There were no differences in the DF profiles of dose–response between males and females. Mirabegron did not inhibit or activateIKASheterologously expressed in human embryonal kidney 293 cells. Reverse transcriptase‐quantitative PCR showed no differences in β‐3 AR expression between sexes. We conclude that mirabegron is antiarrhythmic, and its antiarrhythmic properties are more commonly observed in females than males.imageKey pointsSympathetic nerve activity activates β adrenoceptors to induce cardiac arrhythmia. Among the β adrenoceptors, β‐3 counteracts the effects of β‐1 and β‐2.Mirabegron is an US Food and Drug Administration (FDA)‐approved β‐3 agonist that does not by itself block cardiac ionic currents or prolong the QT interval.We showed that mirabegron significantly prevents wave breaks and reduces the dominant frequency of ventricular fibrillation. These effects are more prominent in female than in male rabbit ventricles.Because the FDA approves mirabegron for human use, its antiarrhythmic effects can be readily tested in humans.
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AbstractThe intrinsic cardiac nervous system (ICNS), termed as the heart's ‘little brain’, is the final point of neural regulation of cardiac function. Studying the dynamic behaviour of these ICNS neurons via multiscale neuronal computer models has been limited by the sparsity of electrophysiological data. We developed and analysed a computational library of neuronal electrophysiological models based on single neuron transcriptomic data obtained from ICNS neurons. Each neuronal genotype was characterized by a unique combination of ion channels identified from the transcriptomic data, using a cycle threshold cutoff that ensured the electrical excitability of the neuronal models. The parameters of the ion channel models were grounded based on passive properties (resting membrane potential, input impedance and rheobase) to avoid biasing the dynamic behaviour of the model. Consistent with experimental observations, the emergent model dynamics showed phasic activity in response to the current clamp stimulus in a majority of neuronal genotypes (61%). Additionally, 24% of the ICNS neurons showed a tonic response, 11% were phasic‐to‐tonic with increasing current stimulation and 3% showed tonic‐to‐phasic behaviour. The computational approach and the library of models bridge the gap between widely available molecular‐level gene expression and sparse cellular‐level electrophysiology for studying the functional role of the ICNS in cardiac regulation and pathology.imageKey pointsComputational models were developed of neuron electrophysiology from single‐cell transcriptomic data from neurons in the heart's ‘little brain’: the intrinsic cardiac nervous system.The single‐cell transcriptomic data were thresholded to select the ion channel combinations in each neuronal model.The library of neuronal models was constrained by the passive electrical properties of the neurons and predicted a distribution of phasic and tonic responses that aligns with experimental observations.The ratios of model‐predicted conductance values are correlated with the gene expression ratios from transcriptomic data.These neuron models are a first step towards connecting single‐cell transcriptomic data to dynamic, predictive physiology‐based models.
AbstractThe vagus nerve is the longest cranial nerve, with much of its territory residing outside the head, in the neck, chest and abdomen. Although belonging to the parasympathetic division of the autonomic nervous system, it is dominated by sensory axons originating in the heart, lungs and airways and the gastrointestinal tract. Electrical stimulation of the cervical vagus nerve via surgically implanted cuff electrodes has been used clinically for the treatment of drug‐resistant epilepsy for three decades but has also shown efficacy in the treatment of drug‐resistant depression and certain gastrointestinal disorders. Through consideration of the anatomical composition of the vagus nerve, its physiology and its distribution throughout the body, we review the effects of vagus nerve stimulation in the context of drug‐resistant epilepsy. This narrative review is divided into two sections: part one surveys the anatomy and physiology of the vagus nerve, and part two describes what we know about how vagus nerve stimulation works.image
AbstractCalciprotein particles (CPPs) are calcium‐ and phosphate‐containing nanoparticles numbers of which are increased in patients with chronic kidney disease (CKD). CPPs have been associated with the development of vascular disease, although the underlying mechanisms are unknown. We previously showed that CPPs induce endothelial cell (EC) dysfunction by reducing nitric oxide (NO) bioavailability and generating superoxide (O2.−). Here, we tested the hypothesis that CPPs induce mitochondrial calcium (Ca2+) overload, which may trigger mitochondrial dysfunction and, consequently, EC activation. Exposure of human umbilical vein ECs to CPPs resulted in significantly increased cytosolic and mitochondrial Ca2+levels compared to vehicle‐treated ECs. Proteome analysis demonstrated impaired endoplasmic reticulum calcium signalling, and decreased enrichment of proteins in the mitochondrial OXPHOS complexes I–III in CPP‐exposed ECs. Respirometry data confirmed these findings and demonstrated decreased basal and maximal respiration in CPP‐exposed ECs. This was accompanied by reduced mitochondrial membrane potential, reduced antioxidant capacity and loss of mitochondria. In the presence of cyclosporin A, a potent mitochondrial permeability transition pore inhibitor, CPP‐induced EC activation and cell death were attenuated. Taken together, our data indicate that CPP‐induced Ca2+overload is an important trigger of mitochondrial dysfunction, and EC activation and cell loss, which eventually may contribute to the development of vascular diseases in CKD. Interventions that target CPP‐induced mitochondrial dysfunction might preserve EC function and possibly alleviate the development of vascular diseases in CKD.imageKey pointsCalciprotein particles (CPPs) are calcium‐ and phosphate‐containing nanoparticles numbers of which are increased in patients with chronic kidney disease and which have been associated with the development of vascular disease.In this study, we tested the hypothesis that CPPs induce mitochondrial calcium (Ca2+) overload in endothelial cells, thereby triggering mitochondrial dysfunction and endothelial activation.We show that exposure of HUVECs (human umbilical vein endothelial cells) to CPPs results in increased cytosolic and mitochondrial Ca2+levels, which is associated with alterations in mitochondrial processes (proteome analysis), cellular respiration, mitochondrial integrity and number.CPP‐induced EC activation and cell death were attenuated in the presence of cyclosporin A, a potent mitochondrial permeability transition pore inhibitor.Our data indicate that CPP‐induced Ca2+overload triggers mitochondrial dysfunction, endothelial activation and cell loss. Interventions that target CPP‐induced mitochondrial dysfunction might preserve EC function in chronic kidney disease.
AbstractObesity is associated with insulin resistance (IR) development, a risk factor for type 2 diabetes (T2D). How mitochondrial bioenergetics, in adipose tissue (AT), differs according to distinct metabolic profiles (i.e. insulin sensitive (IS), IR normoglycaemic (IR‐NG), pre‐diabetes (PD) and T2D) is still poorly understood. The purpose of this study was to evaluate and compare bioenergetics and energy substrate preference by omental AT (OAT) and subcutaneous AT (SAT) from subjects with obesity (OB,n= 40) at distinct metabolic stages. Furthermore, AT bioenergetics was also evaluated pre‐ and post‐bariatric/metabolic surgery (BMS). High‐resolution respirometry (HRR) was used to measure the real‐time oxidative phosphorylation (OXPHOS) capacity and mitochondrial substrate preferences in both tissues. Substrate‐uncoupler‐inhibitor titration protocols were used: SUIT‐P1 (complex I and II‐linked mitochondrial respiration) and SUIT‐P2 (fatty acid oxidation (FAO)‐linked mitochondrial respiration). Flux control ratios (FCRs) were calculated. In SUIT‐P1, lower OXPHOS capacity was observed in AT, particularly in SAT, during the establishment of IR (OB‐IR‐NG) and in the T2D group, due to alterations of mitochondrial coupling, evaluated by FCRs. In SUIT‐P2, the OXPHOS coupling efficiency was highest in the OB‐IR‐NG group. AT from OB‐IS, OB‐IR‐NG and OB‐IR‐PD preferred pyruvate, malate and glutamate oxidation and/or FAO during OXPHOS, whereas AT from T2D preferred succinate oxidation. BMS enhanced mitochondrial respiration in OAT, even under poor OXPHOS coupling efficiency. In conclusion, real‐time OXPHOS analysis by HRR may be a sensitive biomarker of mitochondrial fitness, particularly in AT. Interventions based on modulating energetic substrate availability may become a good tool for obesity treatment stratification.imageKey pointsOmental adipose tissue shows higher oxidative phosphorylation (OXPHOS) capacity compared to subcutaneous adipose tissue in paired explants from subjects with obesity.The OXPHOS capacity of adipose tissue differs through the progression of metabolic disease. Subjects with obesity and diabetes have the lowest OXPHOS capacity in paired explants of subcutaneous and omental adipose tissues.Bariatric surgery enhanced the OXPHOS capacity in omental adipose tissue, even under poor OXPHOS coupling efficiency.Assessment of the oxidative capacity in fresh adipose tissue explants could be a sensitive tool for early diagnosis of metabolic disease.
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AbstractThe intricate role of the autonomic nervous system (ANS) in regulating cardiac physiology has long been recognized. Aberrant function of the ANS is central to the pathophysiology of cardiovascular diseases. It stands to reason, therefore, that neuroscience‐based cardiovascular therapeutics hold great promise in the treatment of cardiovascular diseases in humans. A decade after the inaugural edition, this White Paper reviews the current state of understanding of human cardiac neuroanatomy, neurophysiology and pathophysiology in specific disease conditions, autonomic testing, risk stratification, and neuromodulatory strategies to mitigate the progression of cardiovascular diseases.image
AbstractDopamine is an essential modulator of oxygen sensing and control of ventilation and is the most well described and abundant neurotransmitter in the mammalian carotid body. Little is known of the evolutionary significance of dopamine in oxygen sensing, or whether it plays a similar role in anamniotes. In the model vertebrate, zebrafish (Danio rerio), presynaptic dopamine D2receptor (D2R) expression was demonstrated in gill neuroepithelial cells (NECs), analogues of mammalian oxygen chemoreceptors; however, a mechanism for dopamine and D2R in the gills had not been defined. The present study tested the hypothesis that presynaptic D2Rs provide a feedback mechanism attenuating the chemoreceptor response to hypoxia. Using an isolated gill preparation from Tg(elavl3:GCaMP6s) zebrafish, we measured hypoxia‐induced changes in intracellular Ca2+concentration ([Ca2+]i) in NECs and postsynaptic neurons. Activation of D2R with dopamine or specific D2R agonist, quinpirole, decreased hypoxic responses in NECs; whereas D2R antagonist, domperidone, had the opposite effect. Addition of SQ22536, an adenylyl cyclase (AC) inhibitor, decreased the effect of hypoxia on [Ca2+]i, similar to dopamine. Activation of AC by forskolin partially recovered the suppressive effect of dopamine on the Ca2+response to hypoxia. Furthermore, we demonstrate that the response to hypoxia in postsynaptic neurons was dependent upon innervation with NECs, and was subject to modulation by activation of presynaptic D2R. Our results provide the first evidence of neurotransmission of the hypoxic signal at the NEC‐nerve synapse in the gill and suggest that a presynaptic, modulatory role for dopamine in oxygen sensing arose early in vertebrate evolution.imageKey pointsFor the first time, we present an experimental model that permits imaging of intracellular Ca2+in identified oxygen chemoreceptors in zebrafish using GCaMP in a whole/intact sensing organ.The hypoxic response of zebrafish chemoreceptors is attenuated by dopamine through a mechanism involving D2receptors and adenylyl cyclase.Zebrafish oxygen chemoreceptors send a hypoxic signal to postsynaptic (sensory) neurons.Postsynaptic neuronal responses to hypoxia are modulated by presynaptic D2receptors, suggesting a link between chemoreceptor inhibition by dopamine and modulation of the hypoxic ventilatory response.Our results suggests that a modulatory role for dopamine in oxygen sensing arose early in vertebrate evolution.
AbstractAtrial fibrillation (AF) is a complex arrhythmia. Various modulating factors influence its triggers and substrate. Fibroblasts, adipocytes, inflammatory cells and the coagulation system can disrupt cardiomyocyte function. Cardiomyocytes and fibroblasts release inflammatory cytokines that promote local and systemic inflammation, enhancing fibroblast activation and extracellular matrix deposition, leading to myocardial fibrosis. Fibrosis is essential for the induction of reentrant arrhythmias, including AF. Adipocytes contribute to arrhythmogenesis by secreting pro‐inflammatory and pro‐fibrotic factors, exacerbating inflammation and metabolic dysregulation. Inflammatory mediators activate the coagulation system, which augments this vicious cycle by producing factors promoting inflammation, fibrosis and arrhythmias at the same time as increasing the risk of thrombosis. Understanding these interconnected roles in the development and progress of the atrial arrhythmogenic substrate may point to potential novel therapeutic targets to stabilise or antagonise the atrial substrate and eventually prevent AF. This review examines the role of the interplay between cardiomyocytes, fibroblasts, adipocytes, inflammation and the coagulation system in contributing to the arrhythmogenic substrate for AF initiation and perpetuation.image
AbstractEmerging imaging studies of working memory (WM) have identified significant WM‐related oscillatory events that are unique to each phase of working memory (e.g. encoding, maintenance). Although many previous imaging studies have shown age‐related changes within the frontoparietal network when performing a WM task, understanding of the age‐related changes in the oscillatory dynamics underlying each phase of WM during development and their relationships to other cognitive function is still in its infancy. To this end, we enrolled a group of 74 typically‐developing youths aged 7–15 years to perform a letter‐based Sternberg WM task during magnetoencephalography. Trial‐wise data were transformed into the time‐frequency domain, and significant oscillatory responses during the encoding and maintenance phases of the task were independently imaged using beamforming. Our results revealed widespread age‐related power differences in alpha‐beta oscillatory activity during encoding throughout left frontal, parietal, temporal, occipital and cerebellar regions. By contrast, age‐related differences in maintenance‐related activity were limited to a small area in the superior temporal gyrus and parieto‐occipital regions. Follow‐up exploratory factor analysis of age‐related encoding alpha‐beta activity revealed two distinct factors, and these factors were each found to significantly mediate age‐related improvements in both verbal and non‐verbal cognitive ability. Additionally, late maintenance alpha activity was related to reaction time on the task. Taken together, our results indicate that the neural dynamics in the alpha and beta bands are uniquely sensitive to age‐related changes throughout this developmental period and are related to both task performance and other aspects of cognitive development.imageKey pointsUnderstanding of the age‐related changes in neural oscillatory dynamics serving verbal working memory function is in its infancy.This study identified the age‐related neural alterations during each phase of working memory processing in youths.Developmental differences during working memory processing were primarily isolated to alpha‐beta activity during the encoding phase.Alpha‐beta activity during encoding significantly mediated age‐related improvements in both verbal and non‐verbal ability.This study establishes new brain–behaviour relationships linking working memory function to other aspects of cognitive development.
AbstractMitochondria are a cell's powerhouse and also have a vital part in cellular processes. The emerging role of mitochondria in several crucial processes highlights their cellular and physiological importance. Mitochondrial homeostasis mechanisms, including proteostasis pathways, are vital for mitochondrial health. Failure of these processes has an important role in establishment of numerous complex disease conditions, such as neurodegeneration and imperfect ageing. However, details of mitochondrial impairments and their contribution to the pathology of neurodegeneration are poorly understood. This review systematically discusses the involvement of mitochondrial homeostasis mechanisms and their role in rejuvenating cellular health and fitness. We also focus on various cellular protein quality control mechanisms essential for mitochondrial proteostasis and how their failure leads to mitochondrial functional disturbances observed in disease conditions. We discuss recent findings based on mitostasis‐associated chaperones, mitoproteases, and autophagy responses, which can lead to emergence of new possible therapeutic interventions against complex diseases.image
AbstractElectrogenic transepithelial ion transport can be measured with the short‐circuit current technique. Such experiments are frequently used to evaluate the activity of the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP‐activated chloride channel that is defective in cystic fibrosis, one of the most frequent genetic diseases. Typically, CFTR activity is estimated from the effect of CFTRinh‐172, a selective CFTR inhibitor. Unexpectedly, we found that CFTRinh‐172, in addition to PPQ‐102, another CFTR inhibitor, caused only partial inhibition of CFTR function, particularly in epithelia in pro‐inflammatory conditions, which are characterized by abundant mucus secretion. We hypothesized that the mucus layer was responsible for the poor activity of CFTR inhibitors. Therefore, we treated the epithelial surface with the reducing agent dithiothreitol to remove mucus. Removal of mucus, confirmed by immunofluorescence, resulted in highly enhanced sensitivity of CFTR to pharmacological inhibition. Our results show that the mucus layer represents an important barrier whose presence limits the activity of pharmacological agents. This is particularly relevant for CFTR and the evaluation of therapeutic approaches for correction of the basic defect in cystic fibrosis.imageKey pointsActivity of the cAMP‐activated cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel can be evaluated by measuring the inhibition elicited by the selective blockers CFTRinh‐172 and PPQ‐102.In short‐circuit current recordings on human airway epithelia, CFTR inhibitors had only a partial effect on cAMP‐dependent chloride secretion, suggesting the possible contribution of other ion channels.The mucus layer covering the epithelial surface was removed with the reducing agent dithiothreitol.Treatment of epithelia with dithiothreitol markedly improved the efficacy of CFTR inhibitors.The partial effect of CFTR inhibitors might be explained by the presence of the mucus layer acting as a barrier.
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AbstractPreeclampsia is a hypertensive disorder of pregnancy and is one of the most prevalent causes of maternal and fetal morbidity and mortality. The disease is thought to originate from impaired placental development or restricted villous perfusion, villous constraints and placental senescence at the end of pregnancy, which in turn cause defective placental functioning and eventually systemic endothelial dysfunction. Because the precise pathophysiology of this pregnancy complication is still not clear and diagnosis is only made when it is clinically visible, considerable research is being performed on biomolecules that could play a role in the development of the disease and could have a predictive, diagnostic or prognostic value. In the present review, we focus on two proteins, associated with endothelial dysfunction, which have changed levels in pregnant women during preeclampsia. These two proteins, endothelial specific molecule‐1 (ESM‐1) and guanylate binding protein‐1 (GBP‐1), are known to be involved in processes such as angiogenesis, inflammation and endothelial activation. ESM‐1 is increased during preeclampsia and GBP‐1 is decreased during preeclampsia, and their potential as biomarkers for preeclampsia could therefore be assessed. In addition to assessing their potential to serve as biomarkers, we will go into potential pathophysiological mechanisms of preeclampsia in which these proteins might be involved. We are proposing that ESM‐1 and GBP‐1 might play a role in impaired angiogenesis and vascular maladaptation, impaired immune regulation and oxidative stress, which ultimately could lead to endothelial dysfunction and preeclampsia.image
AbstractSecondary denervation has recently been described as part of the sequela of volumetric muscle loss (VML) injury, occurring along with a significantly elevated neurotrophic response, specifically neuregulin‐1 (NRG1). This may contribute to chronic functional impairments associated with the injury, representing an overlooked treatment target. Thus, though paradoxical, the goal of this study was to pharmacologically reduce neurotrophic signalling after VML using a monoclonal antibody (Herceptin) that inhibits ErbB2 receptors. We also assessed whether ErbB2 inhibition combined with a myogenic treatment (i.e. minced muscle graft) would have a synergistically beneficial effect on function. Adult male Lewis rats underwent surgical induction of tibialis anterior muscle VML injury and were randomized into one of four groups: VML untreated, VML Herceptin, VML muscle graft and VML muscle graft + Herceptin, with comparisons to the contralateral (uninjured) control muscle. Rats receiving Herceptin were administered the drug (8 mg/kgi.p.) at the time of surgery and thrice per week for the duration of the study (48 days). Terminally individual NMJs were quantitatively evaluated, and maximalin vivotorque was tested. ErbB2 inhibition fully restored the normal rates of NMJ innervation and morphology after VML injury, and improved innervation ofde novomyofibres after a muscle‐graft treatment. However ErbB2 inhibition did not improve skeletal muscle function alone or in combination with a muscle‐graft treatment. We conclude that ErbB2 inhibition is a promising therapeutic option for treating VML injury, yet more work is needed to optimize the translation of improved NMJ characteristics to recover function.imageKey pointsIn cases of complex traumatic musculoskeletal injury, such as volumetric muscle loss (VML), the endogenous ability of skeletal muscle to regenerate and recover function is lost.Innervation, or the connection of a motor axon to each individual myofibre, is a necessary component of myofibre survival and contractile function, which is disrupted after VML.Paradoxically a monocolonal antibody inhibitor of neurotrophic signalling (receptor tyrosine kinase ErbB2; Herceptin) has been shown to improve regeneration in rodent models of nerve injury.Here we show that pharmaceutical ErbB2 inhibition following a rat model of VML improves muscle innervation; however it did not correspondingly recover muscle function.Although ErbB2 inhibition alone is an ineffective treatment for VML injury, its ability to improve innervation is noteworthy and should be considered as an adjunctive or combinatorial therapy option.
AbstractThe morphological features of astrocytes are crucial for brain homeostasis, synaptic activity and structural support, yet remain poorly quantified. As a result of the nanometre‐sized cross‐section of neuropil astrocytic processes, electron microscopy (EM) is the only technique availabe to date capable of revealing their finest morphologies. Volume EM (vEM) techniques, such as serial block‐face or focused ion beam scanning EM, enable high‐resolution imaging of large fields and allow more extensive 3‐D model analyses, revealing new astrocytic morphological features. This scoping review aims to summarize the state of the art of astrocyte ultrastructural analysis. This review included 45 of 439 non‐duplicated articles from a Pubmed search, categorizing studies by research focus, animal models, brain region, vEM techniques and segmentation methods. By answering classical questions such as volume, surface area, branching complexity and synaptic ensheathment reported in the literature, this work is a valuable resource for scientists working on structural biology or computational neuroscience.image
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AbstractHeteromeric nicotinic acetylcholine nAChRs (nAChRs) containing the α4 and β2 subunits (α4β2*nAChRs) modulate neurotransmitter release in several regions of the brain. In temporal lobe epilepsy, inhibitory GABAergic neurotransmission is altered, whereas no evidence of nicotinic dysfunction has been reported. Here, we investigated, in human epileptic cortical tissues, the ability of α4β2*nAChRs to modulate synaptic transmission. An increased expression of α4 and β2 subunits was observed in the temporal cortex of epileptic patients. We then recorded excitatory and inhibitory postsynaptic currents from layer 5 pyramidal neurons in the cortex of temporal lobe epilepsy patients, before and during selective modulation of α4β2*nAChRs by desformylflustrabromine (a selective α4β2*positive allosteric modulator). We observed a decrease in both frequency and amplitude of spontaneous excitatory postsynaptic currents, along with an increase in spontaneous inhibitory postsynaptic current frequency. Both these effects were blocked by dihydro‐β‐erythroidine, a selective α4* antagonist. α4β2*activation enhanced the excitability of interneurons (but not of layer 5 pyramidal neurons) by lowering the action potential threshold. Moreover, upon block of action potential propagation by TTX, α4β2*activation did not alter miniature inhibitory postsynaptic currents recorded from pyramidal neurons, at the same time as reducing the release at glutamatergic synapses by a GABAB‐dependent process.imageKey pointsHeteromeric nicotinic acetylcholine receptors containing the α4 and β2 subunits (α4β2*nAChRs) increase GABA release in several regions of the brain.We observe an increase of α4β2*nAChRs expression in the temporal cortex of patients with temporal lobe epilepsy (TLE, the most represented human focal epilepsy).When selectively activated with the positive allosteric modulator desformylflustrabromine (dFBr), α4β2*nAChRs increase the frequency of GABA release and decrease the glutamate release onto pyramidal neurons in the layer 5 of human TLE cortex.The increase of GABA release is related to an α4β2*‐mediated enhanced excitability of cortical interneurons; instead, the decrease of glutamate release involves a presynaptic GABAB‐mediated mechanism, being abolished by a selective GABABblocker.Our findings show that the activation of α4β2*nAChRs induce an increase of the inhibitory tone in human TLE cortex and candidate nicotinic positive allosteric modulators as new pharmacological tools to treat TLE.
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AbstractDiaphragm hyperaemia and regional blood flow distribution are impaired with ageing, potentially consequent to altered vascular structure and/or diminished vasomotor function. Evidence from locomotory skeletal muscle suggests that age‐related diaphragm vasomotor dysfunction may be related to a blunted endothelium‐mediated vasodilatation, decreased nitric oxide (NO) bioavailability and/or augmented reactive oxygen species (ROS) generation. We hypothesized that, in the medial costal diaphragm with old age, there would be fewer feed arteries (FAs) and impaired vasomotor function, via endothelium‐specific mechanisms, in first‐order (1A) arterioles. In young (Y) and old (O) Fischer‐344 rats, the number of medial costal diaphragm FAs was quantified. 1A arterioles (117–220 µm) were isolated, cannulated and pressurized via hydrostatic reservoirs. Thereafter endothelium‐dependent (via ACh) vasodilatory responses were assessed. In a separate set of arterioles, ACh‐mediated dilatation was assessed before and after treatment with the superoxide dismutase mimetic Tempol (100 µm) and Tempol plus the hydrogen peroxide (H2O2) scavenger catalase (100 U/ml). The average number of medial costal FAs was lower in the rat diaphragm with old age (p= 0.001). Endothelium‐ and nitric oxide synthase (NOS)‐dependent vasodilatation was 21% lower in medial costal 1A arterioles from O rats (p< 0.001). Tempol decreased ACh‐mediated vasodilatation of medial costal 1A arterioles from Y and O rats but did not eliminate age‐related differences. Tempol plus catalase further decreased ACh‐mediated vasodilatation in O but not Y vessels. In the medial costal diaphragm vasculature, ageing is associated with (1) arterial rarefaction, (2) impaired endothelium‐dependent vasodilatation via NOS‐ and ROS‐dependent mechanisms and (3) increased reliance on ROS‐mediated vasodilatation.imageKey pointsOld age blunts the hyperaemic response and alters regional blood flow distribution in the diaphragm. The effect of ageing on vascular structure and function in respiratory skeletal muscle is unknown.In young and old Fischer‐344 rats of both sexes, we quantified the number of feed arteries (FAs) and assessed the vasoreactivity of first‐order (1A) arterioles in the medial costal diaphragm.The number of medial costal diaphragm FAs was lower in old rats. In 1A arterioles endothelium‐dependent vasodilatation was blunted, and reactive oxygen species (ROS)‐mediated vasodilatory signalling was greater in old rats.We found no evidence of sex differences in diaphragm macrovascular structure, endothelial function or ROS‐mediated signalling in young or old rats.Our findings in the diaphragm vasculature with ageing provide a mechanistic basis for the age‐related deficits in diaphragm blood flow capacity.Therapeutic interventions targeting the diaphragm vasculature to improve perfusion and oxygen delivery may reduce the burden of age‐related diaphragm dysfunction.
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AbstractGastric vagal afferents (GVAs) sense food‐related mechanical stimuli and signal to the CNS to initiate meal termination. Pregnancy and diet‐induced obesity are independently associated with dampened GVA mechanosensitivity and increased food intake. Whether a high‐fat, high‐sugar diet (HFHSD) impacts pregnancy‐related adaptations in GVA signalling is unknown and was investigated in this study. Three‐week‐old female Glu Venus‐expressing mice, on a C57BL/6 background, were fed standard laboratory diet (SLD) or HFHSD for 12 weeks, and then half of each group were mated to generate late pregnant (Day 17.5; P‐SLDN= 12, P‐HFHSDN= 14) or non‐pregnant (NP‐SLDN= 12, NP‐HFHSDN= 16) groups. Body weight and food intake were monitored in Promethion metabolic cages from before mating until Day 17.5 of pregnancy or equivalent ages in non‐pregnant mice, prior to tissue collection at 07.00 h forin vitrosingle fibre GVA recording and gene expression analysis. Pregnant mice gained more weight than non‐pregnant mice but weight gain was unaffected by diet. By mid‐pregnancy, light‐phase food intake (kJ and g) was higher in pregnant than in non‐pregnant mice (eachP< 0.001) due to larger meals (kJ and g, eachP <0.001), irrespective of diet. Pregnancy and HFHSD‐feeding reduced tension‐sensitive GVA mechanosensitivity (eachP< 0.01), but pregnancy did not further downregulate GVA stretch responses within HFHSD mice (P= 0.652). Nodose ganglia growth hormone receptor mRNA abundance was upregulated in pregnancy, possibly contributing to lower GVA mechanosensitivity during pregnancy in SLD mice. Larger light‐phase meals in pregnant compared to non‐pregnant HFHSD mice may therefore reflect the downregulation of other satiety pathways.imageKey pointsGastric vagal afferents (GVAs) regulate food intake by sensing the arrival and quantity of food and communicating this information to the brain.In standard laboratory diet (SLD) mice, gastric tension‐sensitive vagal afferent mechanosensitivity was attenuated in pregnant compared to non‐pregnant mice, which is concurrent with increases in total food intake and meal size.Nodose ganglia growth hormone receptor mRNA abundance was increased in pregnancy, possibly accounting for attenuated GVA mechanosensitivity in pregnant SLD mice.In non‐pregnant mice, tension‐sensitive GVA mechanosensitivity was selectively attenuated in high‐fat, high‐sugar diet (HFHSD) compared to SLD mice. Despite this, HFHSD mice ate less food and smaller meals compared to the SLD mice, suggesting other satiety mechanisms are limiting food intake.Despite higher food intake, there was no further reduction in mechanosensitivity in pregnant HFHSD mice compared to non‐pregnant HFHSD mice and further studies are required to increase understanding of food intake regulation across pregnancy.
AbstractHomeostatic and Hebbian plasticity co‐operate during the critical period, refining neuronal circuits; however, the interaction between these two forms of plasticity is still unclear, especially in adulthood. Here, we directly investigate this issue in adult humans using two consolidated paradigms to elicit each form of plasticity in the visual cortex: the long‐term potentiation‐like change of the visual evoked potential (VEP) induced by high‐frequency stimulation (HFS) and the shift of ocular dominance induced by short‐term monocular deprivation (MD). We tested homeostatic and Hebbian plasticity independently, then explored how they interacted by inducing them simultaneously in a group of adult healthy volunteers. We successfully induced both forms of plasticity: 60 min of MD induced a reliable change in ocular dominance and HFS reliably modulated the amplitude of the P1 component of the VEP. Importantly, we found that, across participants, homeostatic and Hebbian plasticity were negatively correlated, indicating related neural mechanisms, potentially linked to intracortical excitation/inhibition balance. On the other hand, we did not find an interaction when the two forms of plasticity were induced simultaneously. Our results indicate a largely preserved plastic potential in the visual cortex of the adult brain, for both short‐term homeostatic and Hebbian plasticity. Crucially, we show for the first time a direct relationship between these two forms of plasticity in the adult human visual cortex, which could inform future research and treatment protocols for neurological diseases.imageKey pointsHomeostatic and Hebbian plasticity co‐operate during the critical period to refine neuronal circuits in the visual cortex.The interaction between these two forms of plasticity is still unknown, especially after the closure of the critical periods and in humans.We directly investigate the interplay between Hebbian and homeostatic visual plasticity in adult humans using non‐invasive paradigms.We found a negative correlation between these forms of plasticity showing for the first time a direct relationship between Hebbian and homeostatic plasticity.Our results could inform future research and treatment protocols for neurological diseases.
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AbstractUpper respiratory tract infection (URTI) has a significant economic and social impact and is a major factor compromising athletes’ training and competition. The effects of ColdZyme® Mouth Spray on URTI were investigated using anin vivostudy in athletes, combined with a novelin vitroair–liquid interface human airway model. Endurance athletes were randomised to ColdZyme (n= 78) or placebo (n= 76) and monitored over 3 months. They completed daily symptom and training logs and collected throat swabs over 7 days during perceived URTI.In vitrostudies examined rhinovirus infectivity and epithelial barrier integrity of airway epithelial cells. Eighty‐twoin vivoepisodes were analysed with significantly lower (P= 0.012) episode duration in the ColdZymevs. Placebo group (mean ± SD, 6.2 ± 2.6, (median [interquartile range]) 5.5 [4–9] daysvs. 10.7 ± 10.2, 7.0 [5–11]). There was no difference in incidence (P= 0.149). Training absence and symptom ratings were lower (P< 0.05) in the ColdZyme group. Swabs were returned for 50 episodes, with at least one pathogen detected in all (rhinovirus was most abundant). Absolute quantification (qPCR) for rhinovirus revealed a significantly lower 7‐day area under the curve in ColdZymevs. placebo (median reduction, 94%,P= 0.029).In vitro, viral load was significantly lower (median reductions 80–100%), and epithelial barrier integrity better maintained, and no virus was detected by immunofluorescence analyses of pseudostratified epithelia, with ColdZyme treatment (allP< 0.05). ColdZyme is beneficial for reducing URTI duration, symptom ratings and missed training days. These novel data suggest that the mechanisms involve the protection of epithelial cells against rhinovirus infection and damage.imageKey pointsUpper respiratory tract infections (URTI) are a common complaint in the general population and athletes alike, with social, well‐being and economic consequences, including performance detriments in athletes and reduced work productivity in the general population.Strategies to minimise the risk of contracting a URTI and/or reduce the time taken to clear an infection are desirable to athletes and the general population alike.The present study employed anin vivostudy with athletes in combination with a novelin vitrohuman airway cell model to examine the effects of ColdZyme Mouth Spray on URTI and viral infectivity.The duration for which URTI symptoms persisted was lower with ColdZyme treatment, which also resulted in fewer training absence days.Swabs from participants in thein vivostudy and supernatants from thein vitrostudies showed lower rhinovirus viral load with ColdZyme treatment compared with placebo or control.
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The endoplasmic reticulum (ER) is the largest intracellular Ca2+store, serving as the source and sink of intracellular Ca2+. The ER Ca2+store is continuous yet organized into distinct subcompartments with spatial and functional heterogeneity. In cerebellar Purkinje cells (PCs), glutamatergic inputs trigger Ca2+release from specific ER domains via inositol 1,4,5-trisphosphate receptors (IP3Rs) or ryanodine receptors (RyRs). Upon ER store depletion, refilling occurs through store-operated Ca2+entry mediated by stromal interaction molecule-1 (STIM1). Although the significance of STIM1-mediated Ca2+regulation within PCs is established, STIM1 localization in ER subcompartments in PCs for Ca2+release and refilling remains elusive. Using validated antibodies, we demonstrated that STIM1 was predominantly localized as intense puncta along dendritic shafts in male and female mice, colocalizing with IP3R1 but not with RyR1. Immunoelectron microscopy revealed that STIM1 was accumulated in the subsurface ER in the dendritic shaft but excluded from those in the dendritic spine, the primary site of metabotropic glutamate receptor 1 (mGluR1)-IP3R-mediated Ca²⁺ signaling. Ca²⁺ imaging from control and STIM1-knockdown (STIM1-KD) PCs demonstrated that mGluR1-mediated Ca²⁺ release is more critically dependent on STIM1 than RyR-mediated Ca²⁺ release. These findings reveal a spatially organized ER network in PCs, where specialized ER subcompartments differentially regulate Ca²⁺ release and refilling. These findings suggest that STIM1 preferentially regulates Ca²⁺ dynamics associated with mGluR1-IP3R signaling, supporting specialized ER subcompartments for Ca²⁺ release and refilling. These findings highlight the intricate molecular-anatomical organization of dendritic ER Ca2+signaling in PCs, which is crucial for synaptic plasticity and motor learning.Significance statementIntracellular calcium (Ca²⁺) signaling is essential for neuronal function, yet the organization of endoplasmic reticulum (ER) subcompartments that coordinate Ca²⁺ release and refilling remains unclear. This study demonstrates that stromal interaction molecule-1 (STIM1), a key regulator of store-operated Ca²⁺ entry, is predominantly localized to the subsurface ER in Purkinje cell dendrites, which had not been previously identified. STIM1 colocalizes with inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) and sarco/endoplasmic reticulum Ca²⁺-ATPase 2 (SERCA2) but is segregated from ryanodine receptor 1 (RyR1), highlighting specialized ER subdomains for Ca²⁺ release and refilling. These findings provide new insights into the molecular-anatomical organization of Ca²⁺ signaling in Purkinje cells, which plays key roles in synaptic plasticity, motor learning, and the pathophysiology of neurodegenerative diseases.
RNA-binding proteins (RBPs) are important for post-transcriptional RNA processing, including pre-mRNA alternative splicing, mRNA stability, and translation. Several RBPs have been shown to play pivotal roles in the inner ear, whose dysfunction leads to auditory and/or balance impairments. Epithelial splicing-regulatory protein 1 (ESRP1) regulates alternative splicing and mRNA stability, and mutations inESRP1gene have been associated with sensorineural hearing loss in humans. InEsrp1knockout mouse embryos, alternative splicing of its target genes such asFgfr2is impaired, which eventually result in cochlear development deficits. However,Esrp1knockout mice die soon after birth because of complications from cleft-lip and palate defects, impeding further investigations at later postnatal ages. In the present study, we explored the role of ESRP1 in hearing using zebrafish as a model. We showed thatesrp1and its paralogesrp2are expressed in the inner ear and certain anterior lateral line (ALL) neuromasts. Furthermore, our data suggested that Esrp1 and Esrp2 are required for the mechano-electrical transduction (MET) function of hair cells. RNA sequencing results indicated a significant decrease in the levels of several mRNAs inesrp1/2double knockout larvae. Among the dysregulated genes aretmc1andtmc2a, which encode essential subunits of the MET complex. Further investigations demonstrated that Esrp1/2 could directly bind totmc1andtmc2amRNAs and affect their stability. Taken together, we showed here that Esrp1 and Esrp2 regulate the MET function of zebrafish sensory hair cells by modulating the stability oftmc1andtmc2amRNAs.Significance statementESRP1 is an important RNA-binding protein, whose malfunction has been associated with hearing loss in humans.Esrp1knockout affects alternative splicing of its target mRNAs such asFgfr2,eventually leading to cochlear development deficits in mice. However,Esrp1knockout mice die soon after birth, precluding further investigations at later postnatal ages. In this study, we explored the role of ESRP1 in hearing using zebrafish as a model. Our results demonstrated thatesrp1and its paralogesrp2are expressed in the zebrafish inner ear, and thatesrp1/esrp2double knockout compromised the mechano-electrical transduction (MET) function of hair cells. Additionally, we successfully identifiedtmc1andtmc2amRNAs as the targets of Esrp1/2, which encode essential subunits of the MET complex.
The amygdala is a cluster of subcortical nuclei that receives diverse sensory inputs and projects to the cortex, midbrain, and other subcortical structures. Numerous accounts of amygdalar contributions to social and emotional behavior have been offered, yet an overarching description of amygdala function remains elusive. Here we adopt a computationally explicit framework that aims to develop a model of amygdala function based on the types of sensory inputs it receives, rather than individual constructs such as threat, arousal, or valence. Characterizing human fMRI signal acquired as male and female participants viewed a full-length film, we developed encoding models that predict both patterns of amygdala activity and self-reported valence evoked by naturalistic images. We use deep image synthesis to generate artificial stimuli that distinctly engage encoding models of amygdala subregions that systematically differ from one another in terms of their low-level visual properties. These findings characterize how the amygdala compresses high-dimensional sensory inputs into low-dimensional representations relevant for behavior.Significance StatementThe amygdala is a cluster of subcortical nuclei critical for motivation, emotion, and social behavior. Characterizing the contribution of the amygdala to behavior has been challenging due to its structural complexity, broad connectivity, and functional heterogeneity. Here we use a combination of human neuroimaging and computational modeling to investigate how visual inputs relate to low-dimensional representations encoded in the amygdala. We find that the amygdala encodes an array of visual features, which systematically vary across specific nuclei and relate to the affective properties of the sensory environment.
Compared to males, aggression is less frequently noticed in females. Fierce maternal-aggression to thwart the attack/threat of male-conspecific/intruder is transiently expressed as she defends her pups. The odor cues emanated by the intruder provoke aggressive behavior by robustly activating the ventral-premammillary nucleus (PMv) in the hypothalamic-attack area (HAA). But, how PMv activation triggers aggression is unclear. In view of neuropeptide CART’s potential to reconfigure neural circuits for behavioral demands, occurrence throughout aggression-circuitry, and abundance particularly in PMv, we test the role of PMvCARTin maternal and inter-male aggression in the rats. Males/dams actively attacked the intruder; virgin-females did not. The dams/males without intruder showed isolated cFos-cells in PMv, but intruder’s presence triggered cFos-activation in different PMv-subdivisions in dams/males. Compared to dams without intruder, confrontation with intruder robustly activated PMvCART-neurons, augmented CART-ir in ventral-PMv andcart-mRNA in PMv-containing tissues in dams. Conversely, in males, intruder’s presence activated lateral-PMv CART neurons, but CART-levels remained unaltered. Intra-PMv CART-siRNA administration suppressed maternal-aggression but male-aggression was unaffected. Since PMv is strongly connected with ventrolateral-ventromedial hypothalamus (VMHvl) and medial-preoptic nucleus (MPN), we test whether CART-signalling to these nuclei triggers maternal-aggression. While VMHvl showed stronger CARTergic-axonal input than MPN, immunoneutralization of CART in VMHvl but not MPN, blocked maternal-aggression. CART may drive the circuit beyond HAA since VMHvl neurons contacted by CART-axons project to periaqueductal-gray. We identify engagement of vPMv and lPMv during maternal and inter-male aggression, respectively, and CART as a key mediator in PMv-VMHvl-pathway to express maternal-aggression in rats.Significance statementPregnant/lactating rat transiently become fiercely aggressive to protect her pups when challenged by an intruder. The neural mechanism underlying this transitory expression of aggressive behavior is not clear. We identify the role of neuropeptide CART-containing neurons in the hypothalamic premammillary nucleus (PMv) in dams that gives her the behavioral flexibility to display maternal-aggression. A subset of PMvCARTneurons in dams shows dramatic activation when provoked by an intruder while silencing of these neurons suppressed maternal- but not male-male aggression. Further, CART signals the ventrolateral part of the ventromedial hypothalamus to trigger aggression in dams. The study shows CART as a novel messenger in aggression circuitry and PMvCARTa key regulator of maternal-aggression.
The motor system adapts its output in response to experienced errors to maintain effective movement in a dynamic environment. This learning is thought to utilize sensory prediction errors, the discrepancy between predicted and observed sensory feedback, to update internal models that map motor outputs to sensory states. However, it remains unclearwhatsensory information is relevant (e.g., the extent to which sensory predictions depend on visual feedback features). We explored this topic by measuring the transfer of visuomotor adaptation across two contexts where input movements created visual motion in opposite directions by either: (i) translating a cursor across a static environment or (ii) causing the environment to move towards a static cursor (272 participants: 94 male, 175 female). We hypothesized that this difference in visual feedback should engage distinct internal models, resulting in poor transfer of learning between contexts. Instead, we found nearly complete transfer of learning across contexts, with evidence that the motor memory was bound to the planned displacement of the hand rather than visual features of the task space. Our results suggest that internal model adaptation is not tied to the exact nature of the sensory feedback that results from movement. Instead, adaptation relies on representations of planned movements, allowing a common internal model to be employed across different visual contexts.Significance statementHuman motor control requires constant calibration to remain effective in a dynamic environment. This adaptive process is thought to be driven by error-based learning in internal models that either predict the sensory consequences of a planned movement or output the required movement to realize a sensory goal. However, what sensory information is relevant is unclear. We probed whether internal model adaptation, in response to rotated visual feedback, transferred across two contexts where a common hand movement caused visual motion in opposite directions. We found near-complete transfer of learning across these two contexts, and that learning was tied to hand movements. These results indicate that internal models operate at a level abstracted from the exact nature of the visual feedback provided.
Subplate neurons (SpNs) are among the earliest generated cortical neurons that form functional cortical synapses, and aid in cortical circuit development. A fraction of SpNs survive and form layer 6b in the adult cortex. While SpNs exhibit a large variety of molecular identities, it is unclear if molecular identity correlates with functional or connectomic identities and if different SpNs have similar developmental trajectories. To resolve these questions, we here characterize the functional intracortical circuits to molecularly identified subpopulations of SpNs with SpN-specific Cre-lines (CTGF-dgCre and Drd1-Cre) inin vitrobrain slices of the primary auditory cortex using whole-cell patch clamp recordings and laser-scanning photostimulation. We targeted three age groups: before (postnatal day (P)7-P9) and after (P14-P20) the ear canal opens and when circuits are mature (P60-P80). The excitatory intracortical circuits impinging on both subtypes revealed similar patterns, but not the inhibitory circuits, particularly those from subplate/layer 6b. At P7-P9, Drd1 neurons received stronger inhibition from the subplate compared to CTGF neurons. The functional circuits on SpNs prune with age. By P60-P80, the inhibitory connections from layer 6b on CTGF neurons increased and became significantly abundant than those on Drd1 neurons. However, the inhibition strength between the two subtypes remained unchanged, suggesting that inhibition on CTGF was generally weaker at each stimulation site. Thus, SpNs exhibit diverse neuronal morphologies and intracortical input patterns, independent of molecular expression. Thus, although the subplate comprises distinct molecular classes of neurons, their molecular expression is not clearly correlated with morphologies and functional circuits throughout development.Significance statementSubplate neurons pioneer cortical circuit formation and shape its maturation. Subplate neurons can be categorized into different subpopulation based on their molecular identities. However, the relationship between functional circuitry and molecular identities was unclear. Our study demonstrated that excitatory inputs on different molecular classes of subplate neurons develop similarly but not the inhibitory inputs, particularly those from within subplate/layer6b. Moreover, subplate neurons within the same molecular classes exhibit diverse patterns of intracortical circuit connections and neuronal morphologies. This diversity becomes more pronounced in adulthood. Therefore, distinguishing the functional connectivity between the two subtypes based solely on their molecular identities is impossible. Overall, the molecular expression of subplate neurons is not clearly correlated with their morphologies and functional connectivity pattern.
Perception, working memory, and long-term memory each evoke neural responses in visual cortex. While previous neuroimaging research on the role of visual cortex in memory has largely emphasized similarities between perception and memory, we hypothesized that responses in visual cortex would differ depending on the origins of the inputs. Using fMRI, we quantified spatial tuning in visual cortex while participants (both sexes) viewed, maintained in working memory, or retrieved from long-term memory a peripheral target. In each condition, BOLD responses were spatially tuned and aligned with the target’s polar angle in all measured visual field maps including V1. As expected given the increasing sizes of receptive fields, polar angle tuning during perception increased in width up the visual hierarchy from V1 to V2, V3, hV4, and beyond. In stark contrast, the tuned responses were broad across the visual hierarchy during long-term memory (replicating a prior result) and during working memory. This pattern is consistent with the idea that mnemonic responses in V1 stem from top-down sources, even when the stimulus was recently viewed and is held in working memory. Moreover, in long-term memory, trial-to-trial biases in these tuned responses (clockwise or counterclockwise of target), predicted matched biases in memory, suggesting that the reinstated cortical responses influence memory guided behavior. We conclude that feedback widens spatial tuning in visual cortex during memory, where earlier visual maps inherit broader tuning from later maps thereby impacting the precision of memory.Significance StatementWe demonstrate that remembering a visual stimulus evokes responses in visual cortex that differ in spatial extent compared to seeing the same stimulus. Perception evokes tuned responses in early visual areas that increase in size up the visual hierarchy. Prior work showed that feedback inputs associated with long-term memory originate from later visual areas with larger receptive fields resulting in uniformly wide spatial tuning even in primary visual cortex. We replicate these results and show that the same pattern holds when maintaining in working memory a recently viewed stimulus. That trial-to-trial difficulty is reflected in the accuracy and precision of these representations suggests that visual cortex is flexibly used for processing visuospatial information, regardless of where that information originates.
The medial orbitofrontal cortex (mOFC) has been implicated in shaping decisions involving reward uncertainty, in part by using memories to infer future outcomes. This region is interconnected with other key systems that mediated these decisions, including the basolateral amygdala (BLA) and prelimbic (PL) region of the medial prefrontal cortex, yet the functional importance of these circuits remains unclear. The present study used chemogenetic silencing to examine the contribution of different input and output pathways of the mOFC to risk/reward decision making. Male rats were well-trained on a probabilistic discounting task where they chose between a small/certain (1 pellet) and a large/uncertain 4 pellet option, the odds for which changed systematically across a session. Suppressing activity of descending mOFC terminals in the BLA impaired adjustment in choice biases as reward probabilities change, suggesting this circuit tracks changes in relative value to support flexible reward-seeking. Inhibiting bottom-up BLA→mOFC circuits had no effect on choice. With respect to cortico-cortical circuits, inhibiting mOFC inputs to PL led to more random choice patterns, indicating this circuit promotes advantageous choice by processing context-dependent information regarding wins and losses. In comparison, PL inputs to mOFC attenuates the allure of larger yet uncertain rewards and reduces loss sensitivity, particularly early in the choice sequence. The present findings provide novel insight into the functional contribution that mOFC/BLA and PL interactions make to distinct processes that shape decision making in situations of reward uncertainty.Significance StatementThe medial orbitofrontal cortex supports the use of reward memories to guide efficient value-based decision-making, yet the functional circuits through which it mediates this form of cognition is unclear. The present study revealed that different mOFC interactions with the BLA and the PL facilitate dissociable component processes of decisions involving risks and rewards. These findings clarify the functions of cortico-cortical and cortico-amygdalar pathways and may have implications for understanding how dysfunction in these circuits relates to aberrant decision making seen in certain psychiatric disorders.
Interval timing, the ability of animals to estimate the passage of time, is thought to involve diverse neural processes rather than a single central “clock” (Paton & Buonomano, 2018). Each of the different processes engaged in interval timing follows a different dynamic path, according to its specific function. For example, attention tracks anticipated events, such as offsets of intervals (Rohenkohl & Nobre, 2011), while motor processes control the timing of the behavioral output (De Lafuente et al., 2024). However, which processes are involved and how they are orchestrated over time to produce a temporal decision remains unknown. Here, we study motor preparation in the temporal bisection task, in which Human (Female and male) participants categorized intervals as “long” or “short”. In contrast to typical perceptual decisions, where motor plans for all response alternatives are prepared simultaneously (Shadlen & Kiani, 2013), we find that temporal bisection decisions develop sequentially. While preparation for “long” responses was already underway before interval offset, no preparation was found for “short” responses. Furthermore, within intervals categorized as “long”, motor preparation was stronger at interval offset for faster responses. Our findings support the two-stage model of temporal decisions, where “long” decisions are considered during the interval itself, while “short” decisions are only considered after the interval is over. Viewed from a wider perspective, our study offers methods to study the neural mechanisms of temporal decisions, by studying the multiple processes that produce them.Significance StatementInterval timing is thought to rely on multiple neural processes, yet little is known about which processes are involved, and how they are organized in time. We recorded the EEG of Human participants while they performed a simple temporal decision task, and focused on mu-beta activity, a signature of motor preparation. In typical non-temporal perceptual decisions, mu-beta activity reflects the accumulation of evidence. We find that in temporal decision-making, mu-beta reflects the commitment of the decision instead. This distinction stems from the uniqueness of temporal decisions, in which alternatives are considered sequentially rather than simultaneously. Studying temporal decisions as the dynamic orchestration of multiple neural processes offers a new approach to study the neural mechanisms underlying the perception of time.
Modulation of neuronal oscillations holds promise for the treatment of neurological disorders. Nonetheless, conventional stimulation in a continuous open-loop manner can lead to side effects and suboptimal efficiency. Closed-loop strategies such as phase-locked stimulation aim to address these shortcomings by offering a more targeted modulation. While theories have been developed to understand the neural response to stimulation, their predictions have not been thoroughly tested using experimental data. Using a mechanistic coupled oscillator model, we elaborate on two key predictions describing the response to stimulation as a function of the phase and amplitude of ongoing neural activity. To investigate these predictions, we analyze electrocorticogram recordings from a previously conducted study in Parkinsonian rats, and extract the corresponding phase and response curves. We demonstrate that the amplitude response to stimulation is strongly correlated to the derivative of the phase response ($\rho $> 0.8) in all animals except one, thereby validating a key model prediction. The second prediction postulates that the stimulation becomes ineffective when the network synchrony is high, a trend that appeared missing in the data. Our analysis explains this discrepancy by showing that the neural populations in Parkinsonian rats did not reach the level of synchrony for which the theory would predict ineffective stimulation. Our results highlight the potential of fine-tuning stimulation paradigms informed by mathematical models that consider both the ongoing phase and amplitude of the targeted neural oscillation.Significance StatementThis study validates a mathematical model of coupled oscillators in predicting the response of neural activity to stimulation for the first time. Our findings also offer further insights beyond this validation. For instance, the demonstrated correlation between phase response and amplitude response is indeed a key theoretical concept within a subset of mathematical models. This prediction can bring about clinical implications in terms of predictive power for manipulation of neural activity. Additionally, while phase dependence in modulation has been previously studied, we propose a general framework for studying amplitude dependence as well. Lastly, our study reconciles the seemingly contradictory views of pathologic hypersynchrony and theoretical low synchrony in Parkinson's disease.
Seminal studies in animal neuroscience demonstrate that frontostriatal circuits exhibit a ventral-dorsal functional gradient to integrate neural functions related to reward processing and cognitive control. Prominent neurodevelopmental models posit that heightened reward-seeking and risk-taking during adolescence result from maturational imbalances between frontostriatal neural systems underlying reward processing and cognitive control. The present study investigated whether the development of ventral (VS) and dorsal (DS) striatal resting-state connectivity (rsFC) networks along this proposed functional gradient relates to putative imbalances between reward and executive systems posited by a dual neural systems theory of adolescent development. 163 participants aged 11-25 years (54% female, 90% white) underwent resting scans at baseline and biennially thereafter, yielding 339 scans across four assessment waves. We observed developmental increases in VS rsFC with brain areas implicated in reward processing (e.g., subgenual cingulate gyrus and medial orbitofrontal cortex) and concurrent decreases with areas implicated in executive function (e.g., ventrolateral and dorsolateral prefrontal cortices). DS rsFC exhibited the opposite pattern. More rapid developmental increases in VS rsFC with reward areas were associated with developmental improvements in reward-based decision making, whereas increases in DS rsFC with executive function areas were associated with improved executive function, though each network exhibited some crossover in function. Collectively, these findings suggest that typical adolescent neurodevelopment is characterized by a divergence in ventral and dorsal frontostriatal connectivity that may relate to developmental improvements in affective decision-making and executive function.Significance StatementAnatomical studies in nonhuman primates demonstrate that frontostriatal circuits are essential for integration of neural functions underlying reward processing and cognition, with human neuroimaging studies linking alterations in these circuits to psychopathology. The present study characterized the developmental trajectories of frontostriatal resting state networks from childhood to young adulthood. We demonstrate that ventral and dorsal aspects of the striatum exhibit distinct age-related changes that predicted developmental improvements in reward-related decision making and executive function. These results highlight that adolescence is characterized by distinct changes in frontostriatal networks that may relate to normative increases in risk-taking. Atypical developmental trajectories of frontostriatal networks may contribute to adolescent-onset psychopathology.
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Temporal dynamics play a central role in models of emotion:“fear”is widely conceptualized as a phasic response to certain-and-imminent danger, whereas“anxiety”is a sustained response to uncertain-or-distal harm. Yet the underlying neurobiology remains contentious. Leveraging a translationally relevant fMRI paradigm and theory-driven modeling approach in 220 adult humans, we demonstrate that certain- and uncertain-threat anticipation recruit a shared circuit that encompasses the central extended amygdala (EAc), periaqueductal gray, midcingulate, and anterior insula. This circuit exhibits persistently elevated activation when threat is uncertain and distal, and transient bursts of activation just before certain encounters with threat. Although there is agreement that the EAc plays a critical role in orchestrating responses to threat, confusion persists about the respective contributions of its major subdivisions, the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce). Here we used anatomical regions-of-interest to demonstrate that the BST and Ce exhibit statistically indistinguishable threat dynamics. Both regions exhibited activation dynamics that run counter to popular models, with the Ce showing sustained responses to uncertain-and-distal threat and the BST showing phasic responses to certain-and-imminent threat. For many scientists, feelings are the hallmark of fear and anxiety. Here we used an independently validated multivoxel brain ‘signature’ to covertly probe the moment-by-moment dynamics of anticipatory distress for the first time. Results mirrored the dynamics of neural activation. These observations provide fresh insights into the neurobiology of threat-elicited emotions and set the stage for more ambitious clinical and mechanistic research.Significance statement“Fear”is widely viewed as a phasic response to certain-and-imminent danger, whereas“anxiety”is a sustained response to uncertain-or-distal harm. Prior work has begun to reveal the neural systems recruited by certain and uncertain anticipated threats, but has yet to rigorously plumb the moment-by-moment dynamics anticipated by theory. Here we used a novel combination of neuroimaging techniques to demonstrate that certain and uncertain threat recruit a common threat-anticipation circuit. Activity in this circuit and covert measures of distress showed similar patterns of context-dependent dynamics, exhibiting persistent increases when anticipating uncertain-threat encounters and transient surges just before certain encounters. These observations provide fresh insights into the neurobiology of fear and anxiety, laying the groundwork for more ambitious clinical and mechanistic research.
A promising therapeutic intervention for preventing the onset and progression of Alzheimer's Disease (AD) is to protect and improve synaptic resilience, a well-established early vulnerability associated with the toxic effects of oligomers of Aβ (AβO) and Tau (TauO). We have previously reported that exosomes from hippocampal neural stem cells (NSCs) protect synapses against AβO. Here, we demonstrate how exosomes can also shield against TauO toxicity in adult mice synapses, potentially benefiting primary and secondary tauopathies. Exosomes from hippocampal NSCs (NSCexo) or mature neurons (MNexo) were delivered intracerebroventricularly to adult wildtype male mice (C57Bl6/J). After 24 hours, TauO were administered to suppress long-term potentiation (LTP) and memory, measured by electrophysiology and contextual memory deficits measured using novel object recognition (NOR) test. We also assessed TauO binding to synapses using isolated synaptosomes and cultured hippocampal neurons. Furthermore, mimics of select miRNAs present in NSCexo, were delivered ICV to mice prior to assessment of TauO-induced suppression of hippocampal LTP. Our results showed that NSC-, not MN-, derived exosomes, prevented TauO-induced memory impairment, LTP suppression, and reduced Tau accumulation and TauO internalization in synaptosomes. These findings suggest that NSC-derived exosomes can protect against synaptic dysfunction and memory deficits induced by both AβO and TauO, offering a novel therapeutic strategy for multiple neurodegenerative states.Significance StatementNSCexo provide an unprecedented therapeutic strategy targeting an early vulnerability driven by amyloidogenic toxic oligomers associated with multiple neurodegenerative states.
Our brains are in a constant state of generating predictions, implicitly extracting environmental regularities to support later cognition and behavior, a process known as statistical learning (SL). While prior work investigating the neural basis of SL has focused on the activity of single brain regions in isolation, much less is known about how distributed brain areas coordinate their activity to support such learning. Using fMRI and a classic visual SL task, we investigated changes in whole-brain functional architecture as human female and male participants implicitly learned to associate pairs of images, and later, when predictions generated from learning were violated. By projecting individuals’ patterns of cortical and subcortical functional connectivity onto a low-dimensional manifold space, we found that SL was associated with changes along a single neural dimension describing covariance across the visual-parietal and perirhinal cortex (PRC). During learning, we found regions within the visual cortex expanded along this dimension, reflecting their decreased communication with other networks, whereas regions within the dorsal attention network (DAN) contracted, reflecting their increased connectivity with higher-order cortex. Notably, when SL was interrupted, we found the PRC and entorhinal cortex, which did not initially show learning-related effects, now contracted along this dimension, reflecting their increased connectivity with the default mode and DAN, and decreased covariance with visual cortex. While prior research has linked SL to either broad cortical or medial temporal lobe changes, our findings suggest an integrative view, whereby cortical regions reorganize during association formation, while medial temporal lobe regions respond to their violation.Significance statementThe current work is the first to investigate changes in whole-brain manifold architecture that underlie visual statistical learning (SL). We found that areas of the visual cortex and dorsal attention network showed significant connectivity changes during learning, reflecting their decreased, and increased covariance with other networks, respectively. Notably, when SL was later disrupted, regions within the medial temporal lobe, which had shown no evidence of initial learning, now began to increase connectivity with higher-order cortex. Together, these findings not only reveal the widespread neural interactions that underlie visual SL, but also extend prior work, suggesting separable cortical and medial temporal lobe contributions for the encoding versus violation of learned associations.
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Human performance is endowed by neural representations of information that is relevant for behavior, some of which are also activated in a preparatory fashion to optimize later execution. Most studies to date have focused on highly practiced actions, leaving largely unaddressed the novel re-configuration of information to generate unique whole task-sets. Using electroencephalography (EEG), this study investigated the dynamics of the content and geometry reflected on the neural patterns of control representations during re-configuration of information. We designed a verbal instruction paradigm where each trial involved novel combinations of multi-component task information. By manipulating three task-relevant factors in a sample of 40 participants (26 females, 14 males), we observed complex coding schemes throughout the trial, during both preparation and implementation stages. The temporal profiles were consistent with a hierarchical structure: whereas task information was active in a sustained manner, the coding of more concrete stimulus features was more transient. Data showed both high dimensionality and abstraction, particularly during instruction encoding and target processing. Our results suggest that whenever task content could be recovered from neural patterns of activity, there was evidence of abstract coding, with an underlying geometry that favored generalization. During target processing, where potential interference across stimulus and response factors increased, orthogonal configurations also appeared. Overall, our findings uncover the dynamic manner with which control representations operate during novel recombination unique scenarios, with changes in dimensionality and abstraction adjusting along processing stages.Significance StatementThe neural mechanisms that support task performance in novel contexts have been largely overlooked. Cognitive control is thought to enable complex behavior through the active maintenance of task sets, containing essential information for execution. However, how novel whole combinations of information are organized in neural patterns and their temporal dependencies remain unknown. Here, using a novel complex instruction paradigm, we observed that coding of informational content and its underlying geometry followed a dynamic temporal pattern. Our results reveal varying dimensionality and abstraction throughout the trial, with neural codes generally structured in a geometry favoring generalization of relevant information across task demands. These findings provide a first glimpse into the temporal computations engaged by the brain when encountering novel recombination settings.
The brain builds hierarchical phrases during language comprehension; however, the representational details and dynamics of the phrase-building process remain underspecified. This study directly probes whether the neural code of verb phrases involves reactivating the syntactic property of a key subcomponent (the “head” verb). To this end, we train a part-of-speech sliding-window neural decoder (verb vs. adverb) on EEG signals recorded while 30 participants (17 females) read sentences in a controlled experiment. The decoder reaches above-chance performance that is spatiotemporally consistent and generalizes to unseen data across sentence positions. Appling the decoder to held-out data yields predicted activation levels for the verbal “head” of a verb phrase at a distant non-head word (adverb); the critical adverb appeared either at the end of a verb phrase or at a sequentially and lexically matched position with no verb phrase boundary. There is stronger verb activation beginning at ∼600 milliseconds at the critical adverb when it appears at a verb phrase boundary; this effect is not modulated by the strength of conceptual association between the two subcomponents in the verb phrase nor does it reflect word predictability. Time-locked analyses additionally reveal a negativity waveform component and increased beta-delta inter-trial phase coherence, both previously linked to linguistic composition, in a similar time window. With a novel application of neural decoding, our findings delineate the dynamics by which the brain encodes phrasal representations by, in part, reactivating the representation of key subcomponents. We thus establish a link between cognitive accounts of phrasal representations and electrophysiological dynamics.Significance StatementNeuroimaging studies suggest that the brain constructs hierarchical linguistic representations. However, current evidence does not specify the details of minimal hierarchical units, namely phrases. On the other hand, theoretical consensus postulates phrases represented with properties derived from a key subcomponent, so-called the “head”. Here, we explore the neural code of headed phrases. Leveraging advances in neural decoding, this study introduces a training-prediction pipeline to probe the activation dynamics of the phrasal head in electrophysiological recordings. Our analysis provides novel evidence regarding the neural representation of phrases that, at phrasal boundaries, the head of a phrase is reactivated and integrated into the higher-level representation. This is a fundamental step to understanding the neural bases of language comprehension at the sentence level.
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Sensory systems enable organisms to detect and respond to environmental signals relevant for their survival and reproduction. A crucial aspect of any sensory signal is its intensity; understanding how sensory signals guide behavior requires probing sensory system function across the range of stimulus intensities naturally experienced by an organism. In olfaction, defining the range of natural odorant concentrations is difficult. Odors are complex mixtures of airborne chemicals emitting from a source in an irregular pattern that varies across time and space, necessitating specialized methods to obtain an accurate measurement of concentration. Perhaps as a result, experimentalists often choose stimulus concentrations based on empirical considerations rather than with respect to ecological or behavioral context. Here, we attempt to determine naturally relevant concentration ranges for olfactory stimuli by reviewing and integrating data from diverse disciplines. We compare odorant concentrations used in experimental studies in rodents and insects with those reported in different settings including ambient natural environments, the headspace of natural sources, and within the sources themselves. We also compare these values to psychophysical measurements of odorant detection threshold in rodents, where thresholds have been extensively measured. Odorant concentrations in natural regimes rarely exceed a few parts per billion, while most experimental studies investigating olfactory coding and behavior exceed these concentrations by several orders of magnitude. We discuss the implications of this mismatch and the importance of testing odorants in their natural concentration range for understanding neural mechanisms underlying olfactory sensation and odor-guided behaviors.
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Auditory deviance detection, the neural process by which unexpected stimuli are identified within repetitive acoustic environments, is crucial for survival. While this phenomenon has been extensively studied in the cortex, recent evidence indicates that it also occurs in subcortical regions, including the inferior colliculus (IC). However, compared to animal studies, research on subcortical deviance detection in humans is often constrained by methodological limitations, leaving several important questions unanswered. This study aims to overcome some of these limitations by employing auditory brainstem responses (ABRs) to investigate the earliest neural correlates of deviance detection in humans, with a focus on the IC. We presented healthy participants of either sex with low- and high-frequency chirps in an oddball paradigm and observed significant deviance detection effects in the ABR, specifically when low-frequency chirps were used as deviants within a context of high-frequency standards. These effects manifested as larger and faster ABRs to deviant stimuli, with the strongest responses occurring at higher stimulation rates. Our findings suggest that the human IC exhibits rapid, stimulus-specific deviance detection with differential modulation of response amplitude and latency. The data indicate that the temporal dynamics of novelty detection in humans align well with the data reported in animals, helping to bridge the gap between animal and human research. By uncovering previously unknown characteristics of subcortical deviance detection in humans, this study highlights the value of ABR recordings with excellent temporal resolution in investigating subcortical deviance detection processes.Significance statementAuditory deviance detection enables the brain to identify unexpected stimuli in a repetitive environment, but its subcortical mechanisms in humans remain comparatively underexplored. Using auditory brainstem responses (ABRs), our study reveals two key findings about deviance detection in the human inferior colliculus (IC). First, we show subcortical deviance detection at latencies under 10 ms, bridging a longstanding gap between human and animal research. Second, deviance detection in the IC is rapid, emerging within three or fewer standard repetitions, with differential modulation of ABR amplitude and latency. These findings improve our understanding of the temporal dynamics of auditory processing in the human IC and highlight the value of ABR recordings in studying subcortical deviance detection mechanisms.
High-level perception results from interactions between hierarchical brain systems responsive to gradually increasing feature complexities. During reading, the initial evaluation of simple visual features in the early visual cortex (EVC) is followed by orthographic and lexical computations in the ventral occipitotemporal cortex (vOTC). While similar visual regions are engaged in tactile Braille reading in congenitally blind people, it is unclear whether the visual network maintains or reorganises its hierarchy for reading in this population. Combining fMRI and chronometric transcranial magnetic stimulation (TMS), our study revealed a clear correspondence between sighted and blind individuals (both male and female) on how their occipital cortices functionally supports reading and speech processing. Using fMRI, we first observed that vOTC, but not EVC, showed an enhanced response to lexical vs. non-lexical information in both groups and sensory modalities. Using TMS, we further found that, in both groups, the processing of written words and pseudowords was disrupted by the EVC stimulation at both early and late time windows. In contrast, the vOTC stimulation disrupted the processing of these written stimuli only when applied at late time windows, again in both groups. In the speech domain, we observed TMS effects only for meaningful words and only in the blind participants. Overall, our results suggest that, while the responses in the deprived visual areas might extend their functional response to other sensory modalities, the computational gradients between early and higher-order occipital regions are retained, at least for reading.Significance statementThe sighted visual cortex hierarchically interprets visual signals, from simple visual features in the early visual cortex to complex features in higher-order visual areas. The blind visual cortex is known to respond to tactile and auditory information, but is a similar computational hierarchy used to process these signals? Here we showed that the blind visual cortex processes tactile reading in a spatiotemporal hierarchy strikingly similar to the hierarchy used by the sighted visual cortex to process visual reading. Intriguingly, the blind visual cortex seems additionally involved in the processing of spoken words. Our results suggest that the computational gradients between sensory-deprived early and higher-order areas are largely independent of visual experiences, despite their enhanced responses to crossmodal input.
Fragile X Syndrome (FXS) is a neurodevelopmental disorder that can cause impairments in spatial cognition and memory. The hippocampus is thought to support spatial cognition through the activity of place cells, neurons with spatial receptive fields. Coordinated firing of place cell populations is organized by different oscillatory patterns in the hippocampus during specific behavioral states. Theta rhythms organize place cell populations during awake exploration. Sharp wave-ripples organize place cell population reactivation during waking rest. Here, we examined the coordination of CA1 place cell populations during active behavior and subsequent rest in a rat model of FXS (Fmr1knockout rats). While the organization of individual place cells by the theta rhythm was normal, the coordinated activation of sequences of place cells during individual theta cycles was impaired inFmr1knockout rats. Further, the subsequent replay of place cell sequences was impaired during waking rest following active exploration. Together, these results expand our understanding of how genetic modifications that model those observed in FXS affect hippocampal physiology and suggest a potential mechanism underlying impaired spatial cognition in FXS.Significance StatementFragile X Syndrome (FXS) is a neurodevelopmental disorder that can cause impaired memory and atypical spatial behaviors such as “elopement” (i.e., wandering off and becoming lost). Activity in the CA1 subregion of the hippocampus supports spatial memory and spatial cognition, making it an important candidate to study in the context of FXS; however, how neuronal population activity in CA1 is affected by FXS is poorly understood. In this study, we found that the coordination of populations of CA1 neurons during active behavior and waking rest was impaired in a rat model of FXS. These results reveal hippocampal physiological deficits that may contribute to cognitive impairments in FXS.
In most mammals, conspecific chemical cues that drive innate social and sexual behavior are detected by the vomeronasal organ (VNO) and processed in the accessory olfactory bulb (AOB). Chemosensory stimulation of vomeronasal sensory neurons (VSNs) at their microvillous dendritic knobs triggers, first, a local signal transduction and amplification cascade and, second, transformation of that signal into action potential (AP) discharge at the soma. Both processes ‒ signal transduction and AP generation ‒ involve local Ca2+elevations in the knob and soma, respectively. Here, we revisit the somewhat still controversial functions of Ca2+-activated ion channels in both VSN compartments. In acute mouse VNO slices (of either sex), focal photorelease of Ca2+reveals that VSN knob and soma both act as independent Ca2+signaling compartments, in which Ca2+elevations exert opposite effects. While Ca2+signals in the knob drive an excitatory inward current, Ca2+elevations in the soma primarily activate hyperpolarizing outward currents that silence VSNs. A substantial fraction of the latter current is mediated by SK and / or BK channels. Notably, SK channel activity strongly affects VSN firing. Together, our study reveals a diverse composition of Ca2+-activated currents in VSN somata and uncovers an unexpected role of SK channels in dampening excitability and, thus, in controlling VSN-to-AOB information transfer.Significance StatementCytosolic Ca2+signals play an important role in vomeronasal neuron function. Both sensory signal transduction and information transfer via action potentials involve transient Ca2+elevations. Using local Ca2+uncaging during single-cell electrophysiological recordings, we demonstrate that Ca2+-activated ion channels exert opposite functions during primary transductionversusaction potential firing. Specifically, SK channels are primarily involved in dampening vomeronasal firing.
Memory retrieval activates regions across the brain, including not only the hippocampus and medial temporal lobe (MTL), but also frontal, parietal, and lateral temporal cortical regions. What remains unclear, however, is how these regions communicate to organize retrieval-specific processing. Here, we elucidate the role of theta (3–8 Hz) synchronization, broadly implicated in memory function, during the spontaneous retrieval of episodic memories. Analyzing a dataset of 382 neurosurgical patients (213 male, 168 female, 1 unknown) implanted with intracranial electrodes who completed a free recall task, we find that synchronous networks of theta phase synchrony span the brain in the moments before spontaneous recall, in comparison to periods of deliberation and incorrect recalls. Hubs of the retrieval network, which systematically synchronize with other regions, appear throughout the prefrontal cortex and lateral and medial temporal lobes, as well as other areas. Theta synchrony increases appear more prominently for slow (3 Hz) theta than for fast (8 Hz) theta in the recall–deliberation contrast, but not in the encoding or recall–intrusion contrast, and theta power and synchrony positively correlate throughout the theta band. These results implicate diffuse brain-wide synchronization of theta rhythms, especially slow theta, in episodic memory retrieval.Significance StatementAnalyzing intracranial recordings from 382 subjects who completed an episodic free recall experiment, we study the brain-wide theta synchrony effects of memory retrieval. The literature has not previously described the whole-brain regional distribution of these effects nor studied them with respect to intrusions. We show that a whole-brain theta synchrony effect marks the recall accuracy contrast, that distributed synchronous hubs constitute a whole-brain retrieval network, and that theta synchrony in the successful encoding, successful retrieval, and recall accuracy contrasts correlates positively with theta power increases at a region. These findings advance our understanding of the role and localization of theta synchrony effects during human memory retrieval.
Visual information can have different meanings across species and the same visual stimulus can drive appetitive or aversive behavior. The superior colliculus (SC), a visual center located in the midbrain has been involved in driving such behaviors. Within this structure, the wide-field vertical cell (WFV) is a conserved morphological cell-type that is present in species ranging from reptiles to cats (Basso et al., 2021). Here we report our investigation of the connectivity of the WFV, their visual responses and how these responses are modulated by locomotion in male and female laboratory mice. We also address the molecular definition of these cells and attempt to reconcile recent findings acquired by RNA sequencing of single cells in the SC with the Ntsr1-Cre GN209 transgenic mouse line which was previously used to investigate WFV. We use viral strategies to reveal WFV inputs and outputs and confirm their unique response properties using in vivo two-photon imaging. Among the stimuli tested, WFV prefer looming stimuli, a small moving spot, and upward moving visual stimuli. We find that only visual responses driven by a looming stimulus show a significant modulation by locomotion. We identify several inputs to the WFV as potential candidates for this modulation. These results suggest that WFV integrate information across multiple brain regions and are subject to behavioral modulation. Taken together, our results pave the way to elucidate the role of these neurons in visual behavior and allow us to interrogate the definition of cell-types in the light of new molecular definitions.Significant statementUnderstanding how neuronal response preferences emerge remains a fundamental goal in neuroscience. Our ability to target neuron subpopulations and their embedding in circuits has greatly evolved over the last decades with the development of new tools including transgenic mouse lines and RNA sequencing methods. Here we focus on wide-field vertical cells (WFV) which are found in the superior colliculus, a visual center in the midbrain that is highly conserved across species. Our findings challenge earlier definitions of this cell-type and reconcile them with more modern approaches. Due to their conservation and connectivity, WFV present a model of choice to investigate how neurons gain their response specificity and relationships between structure, function, implication in behavior and molecular profiles.
Previous work has implicated the nucleus accumbens (NAc) in the regulation of effort, defined as the amount of work an animal is willing to perform for a given reward, but little is known about the specific contributions of neuronal populations within the NAc to effort regulation. In this study, using male and female mice, we examined the contributions of direct pathway and indirect pathway neurons in the NAc core using an operant effort regulation task, in which the effort requirement is the number of lever presses needed for earning a food reward. Using optogenetics, we manipulated the activity of direct pathway spiny projection neurons (dSPNs, dopamine D1-like, D1+) and indirect pathway SPNs (iSPNs, adenosine 2A receptor, A2A+). Activating dSPNs reduced lever pressing regardless of the effort requirement, as it elicited gnawing, a competing consummatory behavior. On the other hand, activating iSPNs in the NAc core (but not in the shell) reduced lever pressing in an effort-dependent manner: stimulation-induced reduction in performance was greater at higher press-to-reward ratio requirements. In contrast, optogenetically inhibiting NAc core iSPN output resulted in increased levels of effort exertion. Our results show that the indirect pathway output from the NAc core can bidirectionally regulate effort exertion.Significance statementUsing bidirectional optogenetic manipulation to manipulate direct and indirect pathway neurons in the nucleus accumbens core, we found that activating the direct pathway neurons reduced lever pressing regardless of the effort requirement, as it elicited competing consummatory behaviors like gnawing. On the other hand, activating the indirect pathway neurons in the NAc core reduced lever pressing in an effort-dependent manner: stimulation-inducted reduction in performance was greater at higher press-to-reward ratio requirements.
The orbitofrontal cortex (OFC) plays a crucial role in value-based decisions. While much is known about how OFC neurons represent values, far less is known about information encoded in OFC local field potentials (LFPs). LFPs are important because they can reflect subthreshold activity not directly coupled to spiking, and because they are potential targets for less invasive forms of brain-machine interface (BMI). We recorded neural activity in the OFC of male macaques performing a two-option value-based decision task. We compared the value- and decision-coding properties of high-gamma LFPs (HG, 50-150 Hz) to the coding properties of spiking multi-unit activity (MUA) recorded concurrently on the same electrodes. HG and MUA both represented the values of decision targets, but HG signals had value-coding features that were distinct from concurrently-measured MUA. On average HG amplitude increased monotonically with value, whereas in MUA the value encoding was net neutral on average. HG encoded a signal consistent with a comparison between target values, a signal which was negligible in MUA. In individual channels, HG could predict choice outcomes more accurately than MUA; however, when channels were combined in a population-based decoder, MUA was more accurate than HG. In summary, HG signals reveal value-coding features in OFC that could not be observed from spiking activity, including representation of value comparisons and more accurate behavioral predictions. These results have implications for the role of OFC in value-based decisions, and suggest that high-frequency LFPs may be a viable – or even preferable – target for BMIs to assist cognitive function.Significance statementHigh-frequency LFPs are often assumed to be a mere proxy for local spiking activity. This study finds evidence to the contrary in the OFC of monkeys making value-based decisions. With respect to decision mechanisms, the results challenge previous findings by suggesting a role for OFC in computing value comparisons, evident in a comparison signal encoded in HG but not spiking. More broadly, the results add to the growing evidence for spike/LFP dissociations in prefrontal cortex, and support the idea that HG signals are an important but overlooked resource for identifying neural computations in cognitive tasks. In addition, single-channel HG signals furnished more accurate predictions about choice behavior, supporting the potential use of HG signals in cognitive neural prosthetics.
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AbstractDigital dermatitis (DD) is an endemic infectious hoof disease causing lameness in dairy cattle. The aim of the present study was to investigate the genetic profile of DD development using phenotypic and genotypic data on 2192 Holstein cows. The feet of each cow were clinically examined four times: pre-calving, shortly after calving, near peak of milk production, and in late lactation. Presence or absence of disease and proportion of healthy feet per cow constituted two DD phenotypes of study. For each phenotype and timepoint of clinical examination, we conducted single-step genome-wide association analyses to identify individual markers and genomic regions linked to DD. We focused on the ten 1-Mb windows that explained the largest proportion of the total genetic variance as well as windows that enclosed significant markers. Functional enrichment analysis was also applied to determine functional candidate genes for DD. Significant (P< 0.05) genomic heritability estimates were derived ranging from 0.21 to 0.25. Results revealed two markers on chromosomes 7 and 15 that were related to both disease phenotypes. Furthermore, we identified three genomic windows on chromosome 14 and one window on chromosome 7 each explaining more than 1% of the trait additive genetic variance. Functional enrichment analysis revealed multiple promising candidate genes implicated in hoof health, wound healing, and inflammatory skin diseases. Collectively, our results provide novel insights into the biological mechanism of host resistance to DD development in dairy cattle and support genomic selection towards improving foot health.
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AbstractPerinatal natriophilia has programming effects on blood pressure control, inducing anatomical and molecular changes in the kidney and brain that impair blood pressure reestablishment after a pressor challenge, such as an osmotic stimulation. However, the imprinted effect of voluntary sodium consumption during this period on the development of hypertension is unclear. To evaluate this, we studied the effect of deoxycorticosterone acetate and high-salt diet (DOCA-salt) treatment on blood pressure and sodium intake responses, and gene expression in the kidney and brain in adult offspring exposed to voluntary hypertonic sodium consumption during the perinatal period (PM-NaCl group). Male PM-NaCl rats consumed more sodium than controls (PM-Ctrol group) during DOCA treatment. However, the hypertension induced did not differ between the PM-NaCl and PM-Ctrol groups. This behavioral change was accompanied by a higher angiotensin type 1 receptor (Agtr1a) gene expression at brain level in the subfornical organ and the hypothalamic paraventricular nucleus of PM-NaCl, areas key to the modulation of salt appetite and autonomic function. At renal level, programmed animals showed differing responses in gene expression induced by DOCA-salt treatment compared to the PM-Ctrol group, such as expression ofAgtr1a, transient receptor potential vanilloid type 1 channel in the medulla and vasopressin 2 receptor in the renal cortex. The data indicates that the availability of a rich source of sodium during the perinatal period induces a long-term effect in DOCA-salt treated rats, modifying behavioral, brain and renal responses, suggesting that this early sodium exposure affects the vulnerability of the organisms to chronic non-communicable diseases mainly caused by changes in sodium intake and the regulatory mechanisms of the angiotensin and vasopressin systems.
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AbstractKubernetes has emerged as the backbone of modern cloud-native environments, enabling efficient orchestration of containerized applications. However, its dynamic nature exposes it to sophisticated cyber threats, including privilege escalation, reconnaissance, and denial-of-service attacks. This paper presents a novel framework that combines real-time multi-class threat detection with adaptive deception to enhance Kubernetes security. The framework integrates KServe for scalable machine learning-based threat classification, CICFlowMeter for feature extraction, and KubeDeceive for dynamic deployment of decoys, all governed by the MAPE-K loop for continuous adaptation. Evaluations demonstrate high detection accuracy (up to 91%), efficient resource utilization, and effective attacker engagement, with decoy success rates reaching 93%. The results underscore the framework’s ability to proactively mitigate threats, maintain system resilience, and provide actionable intelligence. This unified approach represents a scalable and adaptable defense mechanism for Kubernetes environments, catering to the needs of dynamic and resource-intensive cloud infrastructures.
AbstractAs basis for evidence-based analgesia refinement, species-specific pharmacokinetic and tolerability profiles of carprofen were determined in rats for least aversive administration routes and prolonged treatment. Further, potential influence on behavioral pain indicators was evaluated. LC-MS/MS determined plasma concentrations in Sprague-Dawley rats (n= 21/sex) after subcutaneous (s.c.) injection (5 mg/kg) and during a 5-day treatment via the drinking water (d.w., 10 mg/kg/24 h). Irwin test parameters, clinical scoring, body weight, body temperature, fluid and food intake, grimace scale, burrowing, nesting, hematology, and histopathology were investigated. Plasma concentrations early after injection were higher in females, reached a maximum (Cmax) of 39.16 ± 7.38 µg/ml at 3 h after injection and remained above an estimated in-vitro-derived therapeutic threshold (24.3 µg/ml) for at least 6 h with a T1/2of 7.06 h. Carprofen-medicated d.w. was readily consumed, with constant target dose intake over the 5-day treatment period reaching a Cmaxof 38.68 ± 8.67 µg/ml at 24 h. Tolerability and behavioral parameters revealed only minor changes, such as transient sedation (s.c.) and decreased body temperature (females). Gastrointestinal adverse effects were not detected. Carprofen’s pharmacokinetic profile allows for a practicable s.c. injection interval. Acceptance and tolerability during prolonged oral treatment with the assessed dose of 10 mg/kg/24 h makes its non-invasive administration promising for analgesia refinement in rats.
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AbstractCracks are common defects in physical structures, and if not detected and addressed in a timely manner, they can pose a severe threat to the overall safety of the structure. In recent years, with advancements in deep learning, particularly the widespread use of Convolutional Neural Networks (CNNs) and Transformers, significant breakthroughs have been made in the field of crack detection. However, CNNs still face limitations in capturing global information due to their local receptive fields when processing images. On the other hand, while Transformers are powerful in handling long-range dependencies, their high computational cost remains a significant challenge. To effectively address these issues, this paper proposes an innovative modification to the VM-UNet model. This modified model strategically integrates the strengths of the Mamba architecture and UNet to significantly improve the accuracy of crack segmentation. In this study, we optimized the original VM-UNet architecture to better meet the practical needs of crack segmentation tasks. Through comparative experiments on the Crack500 and Ozgenel public datasets, the results clearly demonstrate that the improved VM-UNet achieves significant advancements in segmentation accuracy. Compared to the original VM-UNet and other state-of-the-art models, VM-UNet++ shows a 3% improvement in mDS and a 4.6–6.2% increase in mIoU. These results fully validate the effectiveness of our improvement strategy. Additionally, VM-UNet++ demonstrates lower parameter count and floating-point operations, while maintaining a relatively satisfactory inference speed. These improvements make VM-UNet++ advantageous for practical applications.
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AbstractDuchenne muscular dystrophy (DMD), a severe muscle disease caused by mutations in the gene encoding for the intracellular protein dystrophin, is associated with impaired cardiac function and arrhythmias. A causative factor for complications in the dystrophic heart is abnormal calcium (Ca) handling in ventricular cardiomyocytes, and restoration of normal Ca homeostasis has emerged as therapeutic strategy. Here, we used a rodent model of DMD, the dystrophin-deficient DMDmdxrat, to test the following hypothesis: chronic administration of ivabradine (IVA), a drug clinically approved for the treatment of heart failure, improves Ca handling in dystrophic ventricular cardiomyocytes and thereby enhances contractile performance in the dystrophic heart. Intracellular Ca measurements revealed that 4-months administration of IVA to DMDmdxrats significantly improves Ca handling properties in dystrophic ventricular cardiomyocytes. In particular, IVA treatment increased electrically-evoked Ca transients and speeded their decay. This suggested enhanced sarcoplasmic reticulum Ca release and faster removal of Ca from the cytosol. Chronic IVA administration also enhanced the sarcoplasmic reticulum Ca load. Transthoracic echocardiography revealed a significant improvement of cardiac systolic function in IVA-treated DMDmdxrats. Thus, left ventricular ejection fraction and fractional shortening were enhanced, and end-systolic as well as end-diastolic diameters were diminished by the drug. Finally, chronic IVA administration neither significantly attenuated cardiac fibrosis and apoptosis, nor was vascular function improved by the drug. Collectively our findings suggest that long-term IVA administration enhances contractile function in the dystrophic heart by improvement of Ca handling in ventricular cardiomyocytes. Chronic IVA administration may be beneficial for DMD patients.
AbstractWith the explosive growth of terminal devices, scheduling massive parallel task streams has become a core challenge for distributed platforms. For computing resource providers, enhancing reliability, shortening response times, and reducing costs are significant challenges, particularly in achieving energy efficiency through scheduling to realize green computing. This paper investigates the heterogeneous parallel task flow scheduling problem to minimize system energy consumption under response time constraints. First, for a set of independent tasks capable of parallel computation on heterogeneous terminals, the task scheduling is performed according to the computational resource capabilities of each terminal. The problem is modeled as a mixed-integer nonlinear programming problem using a Directed Acyclic Graph as the input model. Then, a dynamic scheduling method based on heuristic and reinforcement learning algorithms is proposed to schedule the task flows. Furthermore, dynamic redundancy is applied to certain tasks based on reliability analysis to enhance system fault tolerance and improve service quality. Experimental results show that our method can achieve significant improvements, reducing energy consumption by 14.3% compared to existing approaches on two practical workflow instances.
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AbstractUni-Travelling-Carrier Photodiodes (UTC-PDs) are pivotal for the advancement of high-speed optical communication systems. Current UTC-PDs have a trade-off between high performance and low production costs. The performance of conventional Ge/Si UTC-PDs is limited by the materials, primarily due to the relatively low electron mobility of Si compared with that of GaAs and InP. The UTC-PDs based on high-mobility materials such as InP have high production and fabrication costs, which limits their effectiveness in next-generation applications. Germanium (Ge) and Gallium Arsenide (GaAs), with their high carrier mobility and lattice-matching capabilities, are strong candidates for UTC-PDs. Their compatibility with GaAs and Si substrates allows for large-scale production and integration into silicon photonics. The Ge/GaAs UTC-PDs are poised to meet the increasing performance demands while keeping production at relatively low costs. This study provides an in-depth analysis and simulation of Ge/GaAs-based UTC-PDs operating at 1550 nm and demonstrates an innovative front-illuminated design. Simulations indicate a 3-dB bandwidth from 30 GHz of up to 54 GHz, responsivity ranging from 0.5 A/W to 0.7 A/W at -2 V, and device diameter between 5 μm and 8 μm. This research opens avenues for a new generation of UTC-PD designs, highlighting the feasibility and potential of the Ge/GaAs material system and providing new options for the development of future photodetectors.
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ABSTRACTTrauma‐focused psychotherapy aims to process intrusive memories in trauma survivors, and sleep is thought to contribute to offline memory consolidation and updating following therapy. We explored associations between posttraumatic stress disorder (PTSD) symptom severity, treatment outcomes and three sleep EEG metrics during posttherapy naps: frequency‐band power, symmetry and spindle to slow oscillation phase‐coupling. These metrics have previously been linked to PTSD symptom severity, emotion regulation in the waking state and memory consolidation, respectively. Data were collected from 17 inpatients with a subthreshold PTSD diagnosis who all suffered from recurring intrusive trauma memories. Patients underwent three sessions of written exposure therapy (WET), a form of trauma‐focused therapy, followed by 90‐min sleep recordings using a portable EEG device. PTSD symptom (PTSS) severity was evaluated using a clinician‐administered interview (CAPS‐5). Initial observations suggest a reduction in EEG power across the Theta, Alpha, Sigma and Gamma bands was observed during deep sleep across WET‐nap sessions, with a low Delta/Alpha ratio potentially predicting symptom change in reexperiencing. Alpha band symmetry correlated with overall PTSS severity but not improvement throughout the course of treatment. Finally, a phase shift in spindle nesting towards the late slow oscillation upstates was found the right hemisphere from WET Sessions 1–3 and correlated with overall PTSS reduction. Although these preliminary findings from our naturalistic clinical sample cannot establish causal relationships due to the lack of appropriate controls, they provide initial insights that may guide future controlled investigations into the complex interplay between sleep physiology and trauma‐focused interventions.
ABSTRACTThe evidence for primary motor cortex reorganization in people with low back pain varies and is conflicting. Little is known about its association with motor and sensory tests, and recovery. We investigated primary motor cortex (re)organization and its associations with motor and sensory tests over time in people with (N= 25) and without (N= 25) low back pain in a longitudinal study with a 5‐week follow‐up. Participants with low back pain received physical therapy. Primary motor cortex organization, including the center of gravity and area of the cortical representation of trunk muscles, was evaluated using neuronavigated transcranial magnetic stimulation, based on individual magnetic resonance imaging. A motor control test (spiral tracking test) and sensory tests (quantitative sensory testing, graphaesthesia, and 2‐point discrimination) were administered. Multivariate mixed models with a 3‐level structure were used. In non‐recovered participants, the center of gravity of longissimus L5 moved significantly anterior, and their temporal summation of pain decreased significantly more than in people without low back pain. The spiral tracking path length decreased significantly in participants without low back pain, which differed significantly from the increase in recovered participants. Significant associations were found between center of gravity and area with quantitative sensory tests and the spiral tracking test. We found a limited number of significant changes and associations over time, mainly related to longissimus L5. For some of these findings, no logical explanation seems currently available. Hence, it is unclear whether meaningful changes in cortical organization occur in people with low back pain over a 5‐week period.
ABSTRACTThe aim of the study was to determine the test–retest reliability of MMN and LDN recorded to simple speech contrasts in children with listening difficulties. MMN and LDN responses were recorded from Fz and Cz electrodes for a /da/‐/ga/ contrast twice within a 10‐day period. To extract MMN and LDN, auditory‐evoked responses to /ga/ stimuli presented alone were subtracted from the responses to /ga/ presented within an oddball sequence. Intraclass correlation coefficients (ICCs) were used to determine test–retest reliability of MMN and LDN. Eighty‐five children aged 7.0–12.8 years were grouped into four clusters; Cluster 1 included children with global difficulties (n= 34); Cluster 2 had children with poor auditory processing but relatively good word reading (n= 19); Cluster 3 had poor auditory processing, memory and attention skills but relatively good nonverbal intelligence and language skills (n= 14); and Cluster 4 had poor auditory processing and attention but relatively good memory skills (n= 18). At Visit 1, MMN and LDN were detectable at Cz in only 42% and 21% of participants, respectively. The ICC for the four clusters for MMN ranged from 0.36 to 0.76; LDN ICCs were 0.21–0.54. MMN was most replicable (71%) for children with listening difficulties in Cluster 3 with good nonverbal intelligence and language. The results do not support the clinical utility of MMN or LDN for objective assessment of auditory discrimination. Although MMN had better test–retest reliability, overall detectability was poor. Better detectability is required for any clinical utility in children.
ABSTRACTA recent paper by Xu et al. proposes that cognitive maps in mice emerge during spatial navigation from path integration anchored to a starting position. We challenge this understanding by arguing that enclosure geometry rather than path integration shapes cognitive maps. Our view emphasizes the context‐specific formation of cognitive maps, claiming that these maps arise in response to particular task demands rather than existing as fixed, independent entities.
ABSTRACTCircadian rhythms influence various physiological and behavioral processes such as sleep–wake cycles, hormone secretion, and metabolism. InDrosophila, an important set of circadian output neurons is called pars intercerebralis (PI) neurons, which receive input from specific clock neurons called DN1. These DN1 neurons can further be subdivided into functionally and anatomically distinctive anterior (DN1a) and posterior (DN1p) clusters. The neuropeptide diuretic hormones 31 (Dh31) and 44 (Dh44) are the insect neuropeptides known to activate PI neurons to control activity rhythms. However, the neurophysiological basis of how Dh31 and Dh44 affect circadian clock neural coding mechanisms underlying sleep inDrosophilais not well understood. Here, we identify Dh31/Dh44‐dependent spike time precision and plasticity in PI neurons. We first find that a mixture of Dh31 and Dh44 enhanced the firing of PI neurons, compared to the application of Dh31 alone and Dh44 alone. We next find that the application of synthesized Dh31 and Dh44 affects membrane potential dynamics of PI neurons in the precise timing of the neuronal firing through their synergistic interaction, possibly mediated by calcium‐activated potassium channel conductance. Further, we characterize that Dh31/Dh44 enhances postsynaptic potentials in PI neurons. Together, these results suggest multiplexed neuropeptide‐dependent spike time precision and plasticity as circadian clock neural coding mechanisms underlying sleep inDrosophila.
ABSTRACTTranscranial alternating current stimulation (tACS) has been proposed to modulate neural activity through two primary mechanisms: entrainment and neuroplasticity. The current study aimed to probe both of these mechanisms in the context of the sensorimotor μ‐rhythm using transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to assess entrainment of corticospinal excitability (CSE) during stimulation (i.e., online) and immediately following stimulation, as well as neuroplastic aftereffects on CSE and μ EEG power. Thirteen participants received three sessions of stimulation. Each session consisted of 90 trials of μ‐tACS tailored to each participant's individual μ frequency (IMF), with each trial consisting of 16 s of tACS followed by 8 s of rest (for a total of 24 min of tACS and 12 min of rest per session). Motor‐evoked potentials (MEPs) were acquired at the start and end of the session (n= 41), and additional MEPs were acquired across the different phases of tACS at three epochs within each tACS trial (n= 90 for each epoch): early online, late online and offline echo. Resting EEG activity was recorded at the start, end and throughout the tACS session. The data were then pooled across the three sessions for each participant to maximise the MEP sample size per participant. We present preliminary evidence of CSE entrainment persisting immediately beyond tACS and have also replicated the plastic CSE facilitation observed in previous μ‐tACS studies, thus supporting both entrainment and neuroplasticity as mechanisms by which tACS can modulate neural activity.
ABSTRACTAudiovisual speech illusions are a spectacular illustration of the effect of visual cues on the perception of speech. Because they allow dissociating perception from the physical characteristics of the sensory inputs, these illusions are useful to investigate the cerebral processing of audiovisual speech. However, the meaningless, monosyllabic utterances typically used to induce illusions are far removed from natural communication through speech. We developed naturalistic speech stimuli that embed mismatched auditory and visual cues within grammatically correct sentences to induce illusory perceptions in controlled fashion. Using intracranial EEG, we confirmed that the cortical processing of audiovisual speech recruits an ensemble of areas, from auditory and visual cortices to multisensory and associative regions. Importantly, we were able to resolve which cortical areas are driven more by the auditory or the visual contents of the speech stimulus or by the eventual perceptual report. Our results suggest that higher order sensory and associative areas, rather than early sensory cortices, are key loci for illusory perception. Naturalistic audiovisual speech illusions represent a powerful tool to dissect the specific roles of individual cortical areas in the processing of audiovisual speech.
ABSTRACTThe late Daniel Kahneman introduced the concept offast and slow thinking, representing two distinct cognitive systems involved in decision‐making (DM). Fast thinking (System 1) operates intuitively and spontaneously. In contrast, slow thinking (System 2) is characterized by deliberation and analytical reasoning. Following Kahneman's view, calledthe biasesview, we suggest a framework involving the interplay between two systems, the bottom‐up and top‐down approaches. These two approaches involve various modalities, including learning skills, perception, cognition, attention, and emotion. Accordingly, we incorporate temporal modulation, which varies based on individual differences and accounts for adaptive DM. Our overarching framework elucidates how the brain dynamically allocates resources for adaptive DM and how creative mental processes could drive it. We highlight the immense value of interdisciplinary research collaboration in progressing the empirical research of our proposed framework.
ABSTRACTBrain information processing complexity is conventionally recognized as derived from neuronal activity, with neurons and their dynamic signalling responsible for the transfer and processing of information. However, the brain also contains other non‐neuronal cells, glial cells, which exceed the number of neurons and are involved in the processes related with information coding by neural networks and underlying brain functions. Decisive advances in the characterization of the molecular and physiological properties of glial cells shed light on their active roles in neurotransmission and neuronal physiopathology. This expanded relationship between neurons and glia challenges traditional neurobiology by highlighting their reciprocal influence, where it is difficult to determine whether neuronal or glial processes initiate and drive the interactions. This interplay creates a dilemma, where the causal hierarchy between these two cell types remains unresolved. A philosophical tool, the ‘Theory of Complexity’ of Edgard Morin can help to better explain and study the complexity of neuron–glia interactions. Morin's proposal on complexity is useful to transform brain knowledge, in order to review the brain molecular functions in antireductionist pattern. In this manuscript, we will discuss how to use the ‘retroactive loop’ principle from Morin's ‘Theory of Complexity’ at the brain molecular level, proposing a new philosophical‐experimental grid that can help neuroscientists for a better understanding of the glia–neuron interactions in the brain.
ABSTRACTAlthough the brain is often characterized as a complex system, theoretical and philosophical frameworks often struggle to capture this. For example, mainstream mechanistic accounts model neural systems as fixed and static in ways that fail to capture their dynamic nature and large set of possible behaviors. In this paper, we provide a framework for capturing a common type of complex system in neuroscience, which involves two main aspects: (i) constraints on the system and (ii) the system's possibility space of available outcomes. Our analysis merges neuroscience examples with recent work in the philosophy of science to suggest that the possibility space concept involves two essential types of constraints, which we call hard and soft constraints. Our analysis focuses on a domain‐general notion of possibility space that is present in manifold frameworks and representations, phase space diagrams in dynamical systems theory, and paradigmatic cases, such as Waddington's epigenetic landscape model. After building the framework with such cases, we apply it to three main examples in neuroscience: adaptability, resilience, and phenomenology. We explore how this framework supports a philosophical toolkit for neuroscience and how it helps advance recent work in the philosophy of science on constraints, scientific explanations, and impossibility explanations. We show how fruitful connections between neuroscience and philosophy can support conceptual clarity, theoretical advances, and the identification of similar systems across different domains in neuroscience.
ABSTRACTThe development of compulsive cue‐controlled‐incentive drug‐seeking habits is a hallmark of substance use disorder that is predicated on an intrastriatal shift in the locus of control over behaviour from a nucleus accumbens (Nac) core–dorsomedial striatum network to a Nac core–anterior dorsolateral striatum (aDLS) network. This shift is paralleled by drug‐induced (including cocaine) dopamine transporter (DAT) alterations originating in the ventral striatum that spread eventually to encompass the aDLS. Having recently shown that heroin self‐administration results in a pan‐striatal reduction in astrocytic DAT that precedes the development of aDLS dopamine‐dependent incentive heroin‐seeking habits, we tested the hypothesis that similar adaptations occur following cocaine exposure. We compared DAT protein levels in whole tissue homogenates, and in astrocytes cultured from ventral and dorsal striatal territories of drug‐naïve male Sprague–Dawley rats to those of rats with a history of cocaine taking or an aDLS dopamine‐dependent incentive cocaine‐seeking habit. Cocaine exposure resulted in a decrease in whole tissue and astrocytic DAT across all territories of the striatum. We further demonstrated that compulsive (i.e., punishment‐resistant) incentive cocaine‐seeking habits were associated with a reduction in DAT mRNA levels in the Nac shell, but not the Nac core‐aDLS incentive habit system. Together with the recent evidence of heroin‐induced downregulation of striatal astrocytic DAT, these findings suggest that alterations in astrocytic DAT may represent a common mechanism underlying the development of compulsive incentive drug‐seeking habits across drug classes.
ABSTRACTLevodopa‐induced dyskinesia (LID) is a common and debilitating complication of long‐term Parkinson's disease treatment. This review explores the roles of NF‐κB and TNF‐α signalling pathways in LID pathophysiology and potential therapeutic approaches targeting these mechanisms. Chronic levodopa treatment leads to aberrant neuroplasticity and neuroinflammation, involving activation of NF‐κB and increased production of pro‐inflammatory cytokines like TNF‐α. NF‐κB activation in glial cells contributes to sustained neuroinflammation and exacerbates dopaminergic neuron loss. TNF‐α levels are elevated in brain regions affected by LID and correlate with dyskinesia severity. Several compounds are involved in mitigating LID by modulating these pathways. Agmatine reduces NF‐κB activation and NMDA receptor expression while protecting dopaminergic neurons. Resveratrol and doxycycline demonstrate antidyskinetic effects by attenuating neuroinflammation and TNF‐α production. The Rho‐kinase (ROCK) inhibitor fasudil and cannabinoid receptor 2 (CB2) receptor agonists also show efficacy in reducing LID severity and neuroinflammation. Hydrogen gas inhalation decreases pro‐inflammatory cytokine levels associated with LID. These findings highlight the complex interplay between NF‐κB, TNF‐α and other neurotransmitter systems in LID pathogenesis. Targeting neuroinflammation and glial activation through these pathways represents a promising strategy for developing novel LID treatments. Further research is needed to fully elucidate the mechanisms and optimize therapeutic approaches targeting NF‐κB and TNF‐α signalling in LID.
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ABSTRACTVerbal fluency provides a unique index of the functional architecture of control functions because it reflects the interactions between executive processes and lower‐level language processes. However, an evaluation of the number of correct words alone does not enable one to determine precisely which processes are impaired. This study investigates post‐stroke fluency impairments, focusing on previously unexplored indices and their neuroanatomical correlates using voxel‐based lesion symptom mapping (VLSM). In total, 337 patients and 851 controls performed letter and semantic fluency tests. Analyses included overall performance (correct responses) and strategic indices (errors, time course, frequency, switches, and cluster size). Stroke patients produced fewer correct responses, more rule‐breaking errors, fewer words after 15″, fewer infrequent words, fewer switches, and smaller clusters in letter fluency. Switching was strongly associated with letter fluency, while clustering was more related to semantic fluency. VLSM identified left‐hemisphere structures, particularly frontal tracts (e.g., anterior thalamic and frontostriatal tracts), associated with switching, and a smaller set of left‐hemisphere structures linked to clustering.Conceptually, the findings suggest stroke‐related fluency disorders primarily arise from impairments in executive strategic search, as indicated by switching impairments, with weaker impairment on lexicosemantic abilities. The rarity of rule‐breaking and perseverative errors indicates that inhibition and working memory deficits do not significantly contribute to poor fluency. The patients' production of infrequent words and fluency worsened over time, although the precise contributions of the three core processes to these additional changes require further investigation. Our results highlight the importance of detailed fluency evaluations in stroke patients for optimized rehabilitation.
ABSTRACTWhen working with sensor‐level data recorded using on‐scalp neuroimaging methods such as electroencephalography (EEG), it is common practice to use two‐dimensional (2D) representations of sensor positions to aid interpretation. Positioning of sensors relative to anatomy, as in the classic 10–20 system of EEG electrode placement, enables the use of 2D topographies that are familiar to many researchers and clinicians. However, when using another increasingly popular on‐scalp neuroimaging method, optically pumped magnetometer–based magnetoencephalography (OP‐MEG), bespoke sensor arrays are much more common, and these are not prepared according to any standard principle. Consequently, polar projection is often used to produce individual sensor topographies that are not directly related to anatomy and cannot be averaged across people simply. Given the current proliferation of OP‐MEG facilities globally, this issue will become an increasing hindrance when visualising OP‐MEG data, particularly for group studies. To address this problem, we adapted and extended the 10–20 system to build a flexible, anatomical projection method applied to digitised head shape, fiducials and sensor positions. We demonstrate that the method maintains spatially veridical representations across individuals improving on standard polar projections at varying OPM sensor array densities. By applying our projection method, the benefits of anatomically veridical 2D topographies can now be enjoyed when visualising data, such as those from OP‐MEG, regardless of variation in sensor placement as in sparse or focal arrays.
ABSTRACTThe subthalamic nucleus (STN) is a key element of the indirect pathway of the basal ganglia (BG) and an effective target for improving motor symptoms in Parkinson's disease (PD) using deep brain stimulation (DBS). While dopamine neuron loss in PD results in a net shift towards increased inhibitory output from the BG, the precise mechanisms by which STN contributes to diminished movement remain unclear due to the complexity and multiplicity of processes underlying response inhibition. We used a modified Go/NoGo task varying uncertainty about Go or NoGo responses to determine how changes in response inhibition are related to STN local field potentials measured in 19 PD patients operated for STN‐DBS. When engaged in the task, low‐frequency band (LFB, 2–7 Hz; including the theta band, 4–7 Hz) power was significantly increased by dopamine treatment. LFB power significantly increased when there was uncertainty about the requirement of executing or withholding a response compared to when a response was certain. Increases in LFB power in individual trials were also significantly associated with faster reaction times. By contrast, beta band (12–30 Hz) power exhibited an inverted profile: It was significantly decreased by dopamine treatment, increased by response certainty and associated with slower reaction times. Our results suggest that STN low‐frequency activity during voluntary behaviour may complement and enhance information obtained from the beta band and should be considered as a possible biomarker for the regulation of inhibition in uncertain contexts.
ABSTRACTMotor axon regeneration after traumatic nerve injuries is a slow process that adversely influences patient outcomes because muscle reinnervation delays result in irreversible muscle atrophy and suboptimal axon regeneration. This advocates for investigating methods to accelerate motor axon growth. Electrical nerve stimulation and exercise both enhance motor axon regeneration in rodents and patients, but these interventions cannot always be easily implemented. A roadblock to uncover novel therapeutic approaches based on the effects of activity is the lack of understanding of the synaptic drives responsible for activity‐mediated facilitation of axon regeneration. We hypothesized that the relevant excitatory inputs facilitating axon regrowth originate in GABA/glycine synapses, which become depolarizing after downregulation of the potassium chloride cotransporter 2 in motoneurons following axotomy. To test this, we injected tetanus toxin (TeTx) into the tibialis anterior (TA) muscle of mice to block the release of GABA/glycine specifically onto TA motoneurons. Thereafter, we axotomized all sciatic motoneurons by nerve crush and analyzed the time courses of muscle reinnervation in TeTx‐treated (TA) and untreated (lateral gastrocnemius [LG]) motoneurons. Muscle reinnervation was slower in TA motoneurons with blocked GABA/glycine synapses, as measured by recovery of M responses and anatomical reinnervation of neuromuscular junctions. Post hoc immunohistochemistry confirmed the removal of the vesicle‐associated membrane proteins 1 and 2 by TeTx activity, specifically from inhibitory synapses. These proteins are necessary for the exocytotic release of neurotransmitters. Therefore, we conclude that GABA/glycine neurotransmission on regenerating motoneurons facilitates axon growth and muscle reinnervation, and we discuss possible interventions to modulate these inputs on regenerating motoneurons.
ABSTRACTObject recognition memory (ORM) is a hippocampus‐dependent form of memory essential for distinguishing items and constructing episodic representations of the past. Ca2+/calmodulin‐dependent protein kinase II (CaMKII) is a serine/threonine‐specific protein kinase highly enriched in the hippocampal formation, where it acts as a memory‐relevant calcium effector. We found that, in rats, training in an ORM inducing learning task rapidly increased CaMKII autophosphorylation in the CA1 region of the dorsal hippocampus. Moreover, early post‐acquisition intra‐dorsal CA1 injection of the substrate‐competitive CaMKII inhibitor AIP impaired long‐term ORM without affecting short‐term ORM or previously consolidated ORMs. The amnesia induced by AIP was replicated by the calmodulin‐competitive CaMKII inhibitor KN93, but not by the inactive analogues of either KN93 or AIP. Notably, these effects occurred regardless of the subject's sex and age or the time of day when learning took place. Together, our findings indicate that hippocampal CaMKII activity is necessary shortly after training for the normal consolidation of ORM.
ABSTRACTHow anodal transcranial direct current stimulation (atDCS) and cathodal tDCS (ctDCS) affect brain networks is still unclear. Previous fMRI studies have yielded controversial results regarding the effects of atDCS and ctDCS on fMRI activation. The present study hypothesizes that the choice of fMRI paradigm may be a contributing factor to this divergence. Therefore, the present study employed two distinct fMRI paradigms, characterized by varying degrees of complexity: finger tapping as a simple fMRI paradigm and an implicit serial reaction time task (SRTT) as a more challenging paradigm. Seventy‐five healthy subjects were randomized to receive either atDCS, ctDCS, or sham stimulation during fMRI. The main effects of the blood oxygenation level–dependent (BOLD) signal were contrasted between groups. SRTT, but not FT, was capable of eliciting differences in modulatory effects on the network between groups. Analysis of functional connectivity between ROIs showed that atDCS and ctDCS shared common and distinct SRTT networks. Correlations between BOLD signal (in ROIs) and the reaction time (RT) recorded during fMRI showed that in the atDCS group, faster RT was associated with higher BOLD signal in the most ROIs, while in the ctDCS group, faster RT was mostly associated with lower BOLD signal activity. The sham group exhibited a combination of these associations. We suggest that atDCS accelerates RT by “pushing” the network, while the network response under ctDCS was a “compensatory” response. The polarity of tDCS differentially modulated the adaptive plasticity of remotely connected regions, based on the concept of functional organization of distributed segregated networks.
ABSTRACTMicroRNAs (miRNAs) have become essential modulators in many brain disorders, such as neurodegenerative diseases, psychiatry disorders, and chronic pain syndromes, and they play a critical role in controlling gene expression. This review investigates how disorders of the nervous system and pain research are affected by malfunctions in the miRNA biogenesis machinery. Despite tremendous progress, we still do not fully understand how these molecular regulators affect neuropathological processes. Even with the increasing amount of research, little is known about the malfunctions of the miRNA machinery, especially when it comes to the nervous system and the diseases that are linked to it. The results of recent research are compiled in this review, which emphasizes the role that disruptions in miRNA processing enzymes, including Drosha, Dicer, Argonaute, and RISC proteins, play in neurological conditions like Parkinson's and Alzheimer's diseases, as well as more general neurodegeneration. We also go over current studies on the stimulus‐dependent, temporal, and spatial expression patterns of these essential miRNA biogenesis components in pain. These discoveries broaden our knowledge of the fundamental processes behind pain‐related illnesses and present prospective directions for focused therapeutic approaches.
ABSTRACTNitrous oxide is a common gaseous anesthetic used in a wide range of medical procedures due to its desirable combination of anesthetic and analgesic properties. Deep brain stimulation surgery, a well‐established treatment for movement disorders like Parkinson's disease, often requires precise microelectrode recordings of the awake brain's electrical signals for optimal results. However, the influence of anesthetics on these brain signals remains a critical consideration. This study investigated how nitrous oxide general anesthesia supplemented by ketamine affects the electrophysiology of the subthalamic nucleus compared to awake and low‐dose ketamine sedation during deep brain stimulation procedures targeting the subthalamic nucleus of Parkinson's disease patients. Spectral analysis of subthalamic nucleus electrophysiological characteristics and statistical analysis of its electrophysiological dimensions were performed on retrospective data from three medical centers. Our findings revealed that nitrous‐ketamine general anesthesia allows electrophysiological subthalamic nucleus identification, despite a slight decrease in overall activity level. Nevertheless, nitrous–ketamine showed significantly lower beta frequency power inside the nucleus compared to the ketamine and awake groups. At the group level, and in many trajectories, delineation of subthalamic nucleus subdomains can be achieved by detection of changes in the delta frequency oscillations. Notably, no differences in electrophysiological nucleus dimensions were found between the three groups. These findings suggest that it is possible to recognize the entrance and exit of the subthalamic nucleus with high confidence under nitrous oxide–ketamine anesthesia. However, the motor subregion of the nucleus is more difficult to delineate under nitrous anesthesia than ketamine sedation or awake, which may affect outcome.
ABSTRACTDeterioration in the peripheral and central auditory systems is common in older adults and often leads to hearing and speech comprehension difficulties. Even when hearing remains intact, electrophysiological data of older adults frequently exhibit altered neural responses along the auditory pathway, reflected in variability in phase alignment of neural activity to speech sound onsets. However, it remains unclear whether challenges in speech processing in aging stem from more fundamental deficits in auditory and timing processes. Here, we investigated if and how aging individuals encoded temporal regularities in isochronous auditory sequences presented at 1.5Hz, and if they employed adaptive mechanisms of neural phase alignment in anticipation of next sound onsets. We recorded EEG in older and young individuals listening to simple isochronous tone sequences. We show that aging individuals displayed larger event‐related neural responses, an increased 1/F slope, but reduced phase‐coherence at the stimulation frequency (1.5Hz) and a reduced slope of phase‐coherence over time in the delta and theta frequency‐bands. These observations suggest altered top‐down modulatory inhibition when processing repeated and predictable sounds in a sequence and altered mechanisms of continuous phase‐alignment to expected sound onsets in aging. Given that deteriorations in these basic timing capacities may affect other higher‐order cognitive processes (e.g., attention, perception, and action), these results underscore the need for future research examining the link between basic timing abilities and general cognition across the lifespan.
ABSTRACTNon‐motor symptoms can severely affect the quality of life of Parkinson's disease‐afflicted patients, with the most common ones being pain, sleep impairments, and neuropsychiatric manifestations. In advanced cases, complex fluctuations of motor and non‐motor symptoms can occur despite optimal medication. Research on deep brain stimulation of the subthalamic nucleus suggests that it may provide benefits for treating non‐motor symptoms in addition to improving motor symptoms. With recent advancements in deep brain stimulation technology, simultaneous recording of local field potentials and delivery of therapeutic stimulation is possible. This opens new possibilities for better understanding the pathophysiology of non‐motor symptoms in Parkinson's disease and for identifying potential electrophysiological biomarkers that accurately represent these symptoms. Specifically, this review aims to highlight potential local field potential biomarkers of non‐motor symptoms in the subthalamic nucleus. The main findings indicate that activities in the beta frequency band are associated with nociception and sleep impairments such as insomnia and rapid eye movement sleep behavior disorders. Additionally, activities in the theta and alpha frequency bands seem to reflect neurocognitive manifestations, including depression and impulse control disorders. A better understanding of these biomarkers could improve the clinical management of non‐motor symptoms in Parkinson's disease. They hold promise for adjusting deep brain stimulation parameters in open‐loop settings and might eventually be applied in closed‐loop deep brain stimulation systems, though their true impact remains uncertain.
ABSTRACTRepetition suppression (RS) refers to the reduction of neuronal responses to repeated stimuli as compared to nonrepeated stimuli. The predictive coding account of RS proposes that its magnitude is modulated by repetition probability (P(rep)) and that this modulation increases with prior experience with the stimulus category. To test these proposals, we examined RS and its modulation by P(rep) for three stimulus categories for which participants had different expertise (Asian faces, written Chinese words and animals) using EEG. Cantonese speakers watched paired stimuli (S1–S2) of a given category with S2 being the same or a different stimulus as S1. Attributes of S1 (e.g., the sex of the first face) served as a cue for the repetition probability of S2. There were significant repetition effects and distinct topographic distributions across stimulus categories. Repetition effects in the N250 component were present in all stimulus categories, but in words, they appeared earlier and showed distinct topographic patterns compared to faces and animals. These results suggest that repetition effects differ between stimulus categories, presumably depending on prior experience and stimulus properties, such as spatial frequency. Importantly, we failed to find evidence for effects of P(rep) across any of the three categories. These null findings of P(rep) effects are putatively indicating an absence of expectancy modulation of repetition effects.
ABSTRACTEpisodic memory benefits from arousal, with better retrieval linked to arousing to‐be‐remembered information. Arousal's impact on subsequent memory processes, particularly for nonarousing stimuli, remains unclear. Healthy ageing is associated with emotion regulation changes and declines in episodic memory, which may influence how arousal affects memory processes. This functional Magnetic Resonance Imaging (fMRI) study examined the effects of valence on episodic memory in young and old adults, focusing on memory of neutral information following arousal exposure. Neural activity was assessed at three time points: during exposure to arousing and nonarousing images, encoding of neutral videos following image exposure, retrieval of the encoded videos. We hypothesised that valence would induce distinct neural activation across task stages, and exposure to negative stimuli would be associated with worse retrieval. Old adults were expected to show stronger neural responses to positive valence and less disruption from negative valence on memory performance. Behavioural results revealed that only negative valence was associated with impaired retrieval. fMRI results replicated age‐related differences in memory performance, with old adults compensating through increased hippocampal and frontal gyri activity. Negative valence was associated with increased activity in the occipital cortex and precentral gyri, also affecting upcoming encoding with heightened activity in the left insula, precuneus and middle temporal gyrus. In old adults, positive valence prompted increasing neural engagement from initial exposure to retrieval, reflecting changes in emotion regulation strategies. Findings emphasise the enduring impact of negative valence on subsequent cognitive processes and suggest that age‐related changes in emotional regulation influence memory‐related neural processes.
ABSTRACTInhibitory control requires individuals to suppress inappropriate behaviors while also engaging in attentional capture of response signals. Previous research has identified the right inferior frontal gyrus as a critical brain region for implementing inhibitory control; however, evidence regarding its role in attentional capture remains limited. Since the Stop trials in the stop signal task involve both attentional capture of salient stimuli and response inhibition, it is challenging to isolate the attentional capture process from inhibitory control. To address this issue, the present study modified the stop signal task by introducing Continue signals, allowing participants to execute Go responses upon seeing a Continue signal. Consequently, the processing of Continue signals involved attentional capture without engaging in response inhibition. Multivoxel pattern analysis revealed that the right inferior frontal gyrus is capable of representing both Stop and Continue signals, with a stronger neural representation for Stop signals compared to Continue signals. Thus, this study demonstrates that the right inferior frontal gyrus is involved in both attentional capture of stimulus signals and behavioral inhibition during the process of inhibitory control. This finding enhances our understanding of the specific functions of the right inferior frontal gyrus in the context of inhibitory control processing.
ABSTRACTThe beam walk is widely used to study coordination and balance in rodents. While the task has ethological validity, the main endpoints of “foot slip counts” and “time to cross” are prone to human‐rater variability and offer limited sensitivity and specificity. We asked if machine learning–based methods could reveal previously hidden, but biologically relevant, insights from the task. Marker‐less pose estimation, using DeepLabCut, was deployed to label 13 anatomical key points on mice traversing the beam. Next, we automated classical endpoint detection, including foot slips, with high recall (> 90%) and precision (> 80%). Using data derived from key point tracking, a total of 395 features were engineered and a random forest classifier deployed that, together with skeletal visualizations, could test for group differences and identify determinant features. This workflow, named Forestwalk, uncovered pharmacological treatment effects in C57BL/6J mice, revealed phenotypes in transgenic mice used to study Angelman syndrome and SLC6A1‐related neurodevelopmental disorder, and will facilitate a deeper understanding of how the brain controls balance in health and disease.
ABSTRACTBody ownership—the perception that one's body belongs to oneself—has been explored using a rubber hand illusion, in which individuals misperceive a fake hand as their own (i.e., embodiment of the fake hand) when an unseen real hand and a visible fake hand are stroked synchronously. Thus, the movement of an embodied fake body may be represented in one's own sensorimotor system. Using a combination of the rubber hand illusion and a motor task, we investigated whether simple movement of the embodied fake hand influenced the subsequent movement of the participants' hand. The participants lifted their own index finger immediately upon observing the index finger lifting on the embodied (rubber hand illusion) or non‐embodied (non‐rubber hand illusion) fake hand (Experiment 1), and a light‐emitting diode turning on near the fake hand (Experiment 2). The reaction times, peak velocities, and peak acceleration were extracted from the participants' finger‐lifting movements. In Experiment 1, the reaction time was significantly shorter in the rubber hand illusion condition than in the non‐rubber hand illusion condition, suggesting the rapid facilitation effect of embodied fake hand movement on actual movement. However, no such motor facilitation was observed in Experiment 2, confirming that the improved reaction time in Experiment 1 resulted from the visual movement of the fake hand rather than attention to the fake hand itself. In contrast to the reaction time, the peak velocity and acceleration did not differ significantly in either experiment. These findings reflect the similar sensorimotor representations of illusory and actual self‐movement.
ABSTRACTHuntington's disease (HD) is a neurodegenerative disorder that presents motor, cognitive, and psychiatric symptoms as it progresses. Prior to motor symptoms onset, alterations, and dysfunctions in the corticostriatal projections have been described along with cognitive deficits, but the sequence of early alterations of brain circuits is largely unknown. There is thus a crucial need to identify early alterations that precede symptoms and that could be used as potential early disease markers. Using an HD knock‐in mouse model (HdhCAG140/+) that recapitulates the human genetic alterations and that shows a late and progressive appearance of anatomical and behavioral deficits, we identified early alterations in the motor learning abilities of young mice, long before any motor coordination dysfunctions. In parallel, ex vivo two‐photon calcium recordings revealed that young HD mice have altered basal activity patterns in both the dorsomedial and dorsolateral parts of the striatum. In addition, although wild‐type mice display specific reorganization of the activity upon motor training, network alterations present in the basal state of non‐trained mice are not affected by motor training of HD mice. Our results thus identify early behavioral deficits and network alterations that could serve as early markers of the disease.
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Background: This study aimed to investigate the diagnostic potential of diffusional kurtosis imaging (DKI) parameters in detecting pathological alterations in the normal-appearing white matter (NAWM) associated with cerebral small vessel disease (CSVD). Methods: A total of 56 patients diagnosed with CSVD were enrolled, all exhibiting confirmed lacunar infarction in the corticospinal tract (CST) as verified by conventional magnetic resonance imaging. A control group of 24 healthy individuals who exhibited no discernible abnormalities on conventional magnetic resonance imaging (MRI) scans was also included. The following DKI parameters were recorded, including mean kurtosis (MK), axial kurtosis (Ka), and radial kurtosis (Kr). Regions of interest were placed at representative levels of the CST on the affected side, encompassing the pons, anterior part of the posterior limb of the internal capsule (PLIC), corona radiata, and subcortex. Results: Variations in MK, Ka, and Kr values in the pons, anterior part of the PLIC, corona radiata, and subcortex of the control group were observed. Notably, the MK and Kr values of the normal-appearing pons in CSVD patients were significantly elevated compared with the control group. The MK, Ka value of the normal-appearing anterior part of the PLIC was significantly higher in the CSVD group than in the control group. The Kr value of the normal-appearing corona radiata exhibited a significant elevation in CSVD patients compared with the control group. Lastly, patients with CSVD displayed lower Ka values and higher Kr values in the normal-appearing subcortex compared with the control group. Conclusions: DKI is an effective tool for assessing NAWM in patients with CSVD. These findings potentially offer novel insights into the prognosis of CSVD and serve as a foundational platform for future DKI studies on NAWM in other diffuse brain lesions.
Background: Ischemic stroke is a prevalent global condition and its associated brain damage poses a significant threat to patient survival and outcomes. The underlying mechanisms of ischemic stroke-induced brain injury remain elusive, necessitating further investigation. Methods: Ischemic stroke models were established using middle cerebral artery occlusion (MCAO) in animals and oxygen-glucose deprivation and reperfusion (OGD-R) in cells. Phospholipase B domain-containing protein 1 (PLBD1) expression in these models was assessed via western blotting analysis, reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR), and cell immunofluorescence. A comprehensive evaluation, incorporating cellular lactate dehydrogenase (LDH) release assays, glycolysis metabolism kits, RT-qPCR, western blotting, triphenyl tetrazolium chloride (TTC) staining, neurological scoring, brain tissue water content measurement, and creatine kinase-MB (CK-MB) analysis, was conducted to determine the impact of PLBD1 on brain injury. Potential lactylation sites in PLBD1 were predicted using the DeepKla database, with western blotting and co-immunoprecipitation (Co-IP) confirming the lactylation site. Results: PLBD1 was significantly upregulated in the brain tissue of MCAO animal models and OGD-R-treated cells. PLBD1 knockdown markedly mitigated OGD-R-induced cellular injury, suppressed glycolysis in vitro, and reversed MCAO-induced brain damage in vivo. Furthermore, lactylation at the K155 site of PLBD1 enhanced its expression in response to elevated lactate levels following OGD-R treatment. These results indicated that the upregulation of PLBD1 via K155 site lactylation plays a pivotal role in exacerbating ischemic stroke-induced brain damage. Conclusion: Targeting the lactate/PLBD1 axis presents a promising therapeutic strategy for ischemic stroke management.
Objectives: This study aimed to investigate the differences between the source localization of the P300 event-related potential (ERP) component among the healthy and mild brain injury (MBI) patient population using standardized low-resolution electromagnetic tomography (sLORETA). Methods: Thirty-eight participants were divided into control (n = 19) and MBI (n = 19) groups. Control participants were normal, healthy people, and participants with MBI were assigned into two groups: MBI 1st Test (7 days after a road traffic accident (RTA)) and MBI 2nd Test (2–6 months after RTA with the same participants of the 1st Test group). The 128-ERP nets were used on the heads of the participants during the experiments. Under the auditory oddball paradigm, all participants silently counted the target tones, while ignoring the standard tones. This study used the sLORETA tool in the Net Station software for the source localization of the P300 ERP component. The Mann-Whitney U test was used to compare intensities between groups, while the Wilcoxon Signed-Rank test was applied for paired observations within groups. Results: Standard stimuli evoked P300 sources in the superior frontal gyrus (BA11) of the right frontal lobe in the control group, the superior temporal gyrus (BA38) of the right temporal lobe in the MBI 1st Test group, and the inferior frontal gyrus (BA47) of the left frontal lobe in the MBI 2nd Test group. Meanwhile, target stimuli evoked P300 sources at BA11 for all groups but in different gyrus: the superior frontal gyrus, orbital gyrus, and rectal gyrus in the control, MBI 1st Test, and MBI 2nd Test groups, respectively. In addition, there were significant differences in dipole intensities between and within groups among control and MBI patients in both standard and target stimuli. Conclusion: P300 source localization was shifted presumably due to the auditory cognitive impairment, and the dipole intensities were significantly higher in the MBI group than in the control group, indicating that the MBI group compensated for both standard and target tone stimuli, reflected in the sLORETA investigation.
Background: Parkinson’s Disease (PD) is associated with dysregulated/chronic inflammation. The immune system has multiple roles including beneficial effects such as clearing alpha synuclein aggregates. However, peripheral immune cells entering the brain may also contribute to inflammation and neurodegeneration. To identify which cells might have a negative impact and could be potential therapeutic targets, we compared immune signatures of patients and healthy controls. Methods: Multicolor flow cytometry was used to determine the frequencies of major immune cell subsets in peripheral blood mononuclear cells (PBMCs) of PD patients and controls. Because of the major impact of Cytomegalovirus (CMV) infection on the distribution of immune cell subsets, particularly cluster of differentiation (CD)8+ T-cells, all participants were tested for CMV seropositivity. Results: Although the cohort of 35 PD patients exhibited the well-established T-cell differentiation signature driven by CMV infection, there were no differences in the frequencies of differentiated or pro-inflammatory T-cells, B-cells or natural killer cells (NK-cells) attributable to the disease. However, percentages of myeloid-derived suppressor cells (MDSCs) were higher in PD patients than controls. Moreover, percentages of CD14+CD16+ (intermediate) monocytes expressing the C-C chemokine receptor type 5 (CCR5) correlated with disease severity assessed by the Movement Disorder Society’s revised version of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) score and disease duration. Conclusions: A comprehensive evaluation of the major subsets of circulating immune cells in PD patients revealed differences in myeloid cells between PD and healthy controls and some correlation of monocyte abundance with disease severity.
Background: Several preclinical studies have reported elevated levels of tau following the induction of chronic cerebral hypoperfusion (CCH) in Alzheimer’s disease mouse models. The objective of this study was to first induce CCH in a mouse model of tauopathy over an extended period of up to 6 months and to subsequently investigate the effects of CCH on tau accumulation and alterations in the transcriptome. Methods: Three-month-old P301S tauopathy mice were randomly allocated to either a Sham or CCH group. The common carotid arteries (CCAs) of the CCH group were bilaterally implanted using 0.75-mm inner diameter ameroid constrictors. Prior to surgery, Doppler ultrasound imaging was acquired, with follow-up imaging at 1, 3, and 6 months postoperatively. Brain tissue samples were obtained, and hemispheres were dissected and divided for separate analysis. Result: No significant differences in phosphorylated and total tau protein levels were found in either Sham or CCH left cortical hemispheres or hippocampal lysates. Immunohistochemical staining of phosphorylated tau in the right hemisphere revealed similar findings. Compared with the Sham group, transcriptomic deconvolution revealed a significant reduction of memory B cells in the CCH group (p = 0.029). Conclusion: To clarify the effects of chronic hypoperfusion on tau pathology, more than one surgical method of hypoperfusion should be used in future studies.
Background: Multiple sclerosis (MS) is a neurodegenerative disorder characterized by progressive motor and cognitive impairments, affecting millions worldwide. It significantly reduces patients’ quality of life and imposes a burden on health systems. Despite advances in understanding MS, there is no cure, highlighting the need for effective therapeutic strategies. Preclinical animal models are critical for gaining insights into MS pathophysiology and treatments. However, these models fail to fully replicate the complexity of human MS, making it essential to choose appropriate models and behavioral tests to evaluate their efficacy. Purpose: This review examines various motor and cognitive behavioral tests used in preclinical MS models, discussing their strengths and limitations. The goal is to guide researchers in selecting the most appropriate tests for their models, while providing insights into how these tests are performed and analyzed. Methods: We reviewed motor and cognitive behavioral tests used in MS models, detailing test procedures and evaluating their advantages and disadvantages. Results: This review offers a comprehensive overview that aids researchers in choosing the most suitable tests for their studies, improving the accuracy and reliability of preclinical MS research. Conclusions: Understanding the strengths and limitations of these tests is crucial for making informed decisions, leading to better experimental designs and, ultimately, more effective therapeutic interventions for MS.
Background: Vitamin D (VitD) deficiency is prevalent in more than half of patients treated with antiepileptic drugs. The number of seizures decreases by more than 40% after vitamin D3 supplementation. This study aimed to investigate the antiepileptic effects of vitamin D3 by using an in vivo epileptic model. Method: Sprague–Dawley rats received pentylenetetrazole (i.p.) treatment to induce epilepsy and were then treated with sodium valproate, VitD, or a combination of VitD and paricalcitol. Results: Vitamin D3 treatment improved epileptic behavior, as evidenced by increased latency time and a significant reduction in epileptic scores on the seventh day after pentylenetetrazole challenge. Improvements in cell morphology and reduced neuronal damage were observed as well as decreased apoptosis rates caused by epilepsy. Although no significant changes in the calcium-sensing receptor (CaSR) were observed in any group, the level of VitD receptor (VDR) significantly increased in groups treated with vitamin D3 alone, and with paricalcitol and sodium valproate. Conclusions: The study demonstrated the effect of vitamin D3 on reducing neuronal damage caused by epilepsy. The neuroprotective effects of vitamin D3 treatment may be attributed to the inhibition of cell apoptosis and the increase in the expression of VitD receptors induced by epilepsy.
Neuroregulatory therapy, encompassing deep brain stimulation and responsive neurostimulation, is increasingly gaining attention for the treatment of drug-resistant temporal and occipital lobe epilepsy. Beyond the approved anterior nucleus of the thalamus, the pulvinar nucleus of the thalamus is a potential stimulation target. Through a confluence of animal studies, electrophysiological research, and imaging studies, the pulvinar has been identified as having extensive connections with the visual cortex, prefrontal cortex, limbic regions, and multimodal sensory associative areas, playing a pivotal role in multisensory integration and serving as a propagation node in both generalized and focal epilepsy. This review synthesizes recent research on the pulvinar in relation to cortical and epileptic networks, as well as the efficacy of neuroregulatory therapy targeting the pulvinar in the treatment of temporal and occipital lobe epilepsy. Further research is warranted to elucidate the differential therapeutic effects of stimulating various subregions of the pulvinar and the specific mechanisms underlying the treatment of epilepsy through pulvinar stimulation.
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Cerebral small vessel disease is a common disease endangering human health due to its insidious and repeated onset and progressive aggravation. White matter hyperintensities (WMHs) are one of the classic imaging markers of cerebral small vessel disease. The term ‘WMHs’ was first proposed by Hachinski in 1987. The WMHs in our study mainly refer to cerebral white matter damage caused by various vascular factors, known as vascularized white matter hyperintensity. WMHs are significantly correlated with stroke, cognitive dysfunction, emotional disturbance, and gait abnormality, and have drawn widespread attention. This article reviews the research progress on the pathogenesis of cognitive dysfunction associated with WMHs and provides a theoretical reference for understanding the pathogenesis of WMHs and the early assessment of associated cognitive dysfunction.
Background: Major Depressive Disorder (MDD) patients exhibit difficulty in forgetting negative material, which may result from specific impairments in memory and attention. However, the underlying neural correlates of the corresponding cognitive deficit have not been elucidated. The present study investigated the electrophysiological characteristics and differences, using event-related potentials (ERPs), between MDD patients and healthy controls (HCs) in an emotional directed forgetting task (EDF) with negative and neutral images. Methods: A total of 26 MDD patients and 28 HCs were recruited for the current study, all of whom were clinically evaluated using the Hamilton Depression Scale. All participants were subjected to ERP measurements during the EDF task, and behavioral data and ERP components were analyzed. Results: HCs had higher hit rates than did MDD patients; more false alarms occurred in MDD patients than in HCs, and higher false alarm rates occurred with negative images than with neutral images. The reaction times were also longer for MDD patients than for HCs. Larger image-evoked P2 amplitudes and smaller image-evoked N2 amplitudes occurred in MDD patients, whereas they had higher image-evoked late positive potential (LPP) amplitudes both in negative and neutral emotional conditions than the HCs. MDD patients had higher cue-evoked N2 amplitudes and lower cue-evoked P3 amplitudes, elicited by the Remember cue, than the HCs. The Hamilton Depression Rating Scale (24-item edition) scores were positively correlated with the LPP amplitudes that were evoked by negative images in a central location. Conclusions: Based on these results, we concluded that poor attentional recruiting and allocation, memory inhibitory deficits, and difficulties in memory retention may contribute to the poor performance in the EDF task in MDD patients. The observed ERP patterns provide valuable insights into the neural mechanisms underlying the EDF task in MDD and underscore the potential of EDF as an assessment tool for cognitive and emotional dysregulation in MDD.
This paper offers a syncretic synthesis of the highlights of the scientific knowledge accumulated to date on the mechanisms of infantile amnesia (IA). IA can be conceptualized as a meta-norm of memory development. The review shows that the neurobiological and neuropsychological evidence for IA converges within a common metacognitive framework of inquiry. The involvement of consciousness in the conditioning of memory traces and the association between infantile knowledge and implicit memory allow IA to be analyzed as a phenomenon with complex, universal neuropsychic regulation of a higher order. This approach overcomes the paradox of understanding IA.
Microglia play a crucial role in monitoring the microenvironment of the central nervous system. Over the past decade, the role of microglia in the field of pain has gradually been unraveled. Microglia activation not only releases proinflammatory factors that enhance nociceptive signaling, but also participates in the resolving of pain. Opioids induce microglia activation, which enhances phagocytic activity and release of neurotoxic substances. Conversely, microglia activation reduces opioid efficacy and results in opioid tolerance. The application of microglia research to clinical pain management and drug development is a promising but challenging area. Microglia-targeted therapies may provide new avenues for pain management.
Background: This study investigates the reliability of functional near-infrared spectroscopy (fNIRS) in detecting resting-state brain network characteristics in patients with mild cognitive impairment (MCI), focusing on static resting-state functional connectivity (sRSFC) and dynamic resting-state functional connectivity (dRSFC) patterns in MCI patients and healthy controls (HCs) without cognitive impairment. Methods: A total of 89 MCI patients and 83 HCs were characterized using neuropsychological scales. Subject sRSFC strength and dRSFC variability coefficients were evaluated via fNIRS. The study evaluated the feasibility of using fNIRS to measure these connectivity metrics and compared resting-state brain network characteristics between the two groups. Correlations with Montreal Cognitive Assessment (MoCA) scores were also explored. Results: sRSFC strength in homologous brain networks was significantly lower than in heterologous networks (p < 0.05). A significant negative correlation was also observed between sRSFC strength and dRSFC variability at both the group and individual levels (p < 0.001). While sRSFC strength did not differentiate between MCI patients and HCs, the dRSFC variability between the dorsal attention network (DAN) and default mode network (DMN), and between the ventral attention network (VAN) and visual network (VIS), emerged as sensitive biomarkers after false discovery rate correction (p < 0.05). No significant correlation was found between MoCA scores and connectivity measures. Conclusions: fNIRS can be used to study resting-state brain networks, with dRSFC variability being more sensitive than sRSFC strength for discriminating between MCI patients and HCs. The DAN-DMN and VAN-VIS regions were found to be particularly useful for the identification of dRSFC differences between the two groups. Clinical Trial Registration: ChiCTR2200057281, registered on 6 March, 2022; https://www.chictr.org.cn/showproj.html?proj=133808.
Background: Autism spectrum disorder (ASD) has been reported to confer an increased risk of natural premature death. Telomere erosion caused by oxidative stress is a common consequence in age-related diseases. However, whether telomere length (TL) and oxidative indicators are significantly changed in ASD patients compared with controls remains controversial. The aim of this study was to determine the associations of ASD with TL and oxidative indicators by performing a meta-analysis of all published evidence. Methods: The PubMed and Embase databases were searched for articles published up to April, 2024. The effect size was expressed as standardized mean difference (SMD) and 95% confidence interval (CI) via Stata 15.0 software. Results: Thirty-nine studies were included. Pooled results showed that compared with controls, children and adolescents with ASD were associated with significantly shorter TL (SMD = –0.48; 95% CI = –0.66– –0.29; p < 0.001; particularly in males), lower total antioxidant capacity (TAC: SMD = –1.15; 95% CI = –2.01– –0.30; p = 0.008), and higher oxidative DNA (8-hydroxy-2′-deoxyguanosine, 8-OHdG: SMD = 0.63; 95% CI = 0.03–1.23; p = 0.039), lipid (hexanolyl-lysine, HEL: SMD = 0.37; 95% CI = 0.13–0.62; p = 0.003), and protein (3-nitrotyrosine, 3-NT: SMD = 0.86; 95% CI = 0.21–1.51; p = 0.01; dityrosine, DT: SMD = 0.66; 95% CI = 0.521–0.80; p < 0.01) damage. There were no significant differences between ASD and controls in 8-isoprostane and oxidative stress index after publication bias correction, and in N-formylkynurenine during overall meta-analysis. Conclusions: TL, 8-OHdG, TAC, HEL, 3-NT, and DT represent potential biomarkers for prediction of ASD in children and adolescents.
Background: White matter (WM) is a principal component of the human brain, forming the structural basis for neural transmission between cortico-cortical and subcortical structures. The impairment of WM integrity is closely associated with the aging process, manifesting as the reorganization of brain networks based on graph theoretical analysis of complex networks and increased volume of white matter hyperintensities (WMHs) in imaging studies. Methods: This study investigated changes in the robustness of WM brain networks during aging and assessed their correlation with WMHs. We constructed WM brain networks for 159 volunteers from a community sample dataset using diffusion tensor imaging (DTI). We then calculated the robustness of these networks by simulating neurodegeneration based on network attack analysis, and studied the correlations between WM network robustness, age, and the proportion of WMHs. Results: The analysis revealed a moderate, negative correlation between WM network robustness and age, and a weak and negative correlation between WM network robustness and the proportion of WMHs. Conclusions: These findings suggest that WM pathologies are associated with aging and offer new insights into the imaging characteristics of the aging brain.
Background: Volume alterations in the parietal subregion have received less attention in Alzheimer’s disease (AD), and their role in predicting conversion of mild cognitive impairment (MCI) to AD and cognitively normal (CN) to MCI remains unclear. In this study, we aimed to assess the volumetric variation of the parietal subregion at different cognitive stages in AD and to determine the role of parietal subregions in CN and MCI conversion. Methods: We included 662 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, including 228 CN, 221 early MCI (EMCI), 112 late MCI (LMCI), and 101 AD participants. We measured the volume of the parietal subregion based on the Human Brainnetome Atlas (BNA-246) using voxel-based morphometry among individuals at various stages of AD and the progressive and stable individuals in CN and MCI. We then calculated the area under the curve (AUC) of the receiver operating characteristic (ROC) curve to test the ability of parietal subregions to discriminate between different cognitive groups. The Cox proportional hazard model was constructed to determine which specific parietal subregions, alone or in combination, could be used to predict progression from MCI to AD and CN to MCI. Finally, we examined the relationship between the cognitive scores and parietal subregion volume in the diagnostic groups. Results: The left inferior parietal lobule (IPL)_6_5 (rostroventral area 39) showed the best ability to discriminate between patients with AD and those with CN (AUC = 0.688). The model consisting of the left IPL_6_4 (caudal area 40) and bilateral IPL_6_5 showed the best combination for predicting the CN progression to MCI. The left IPL_6_1 (caudal area 39) showed the best predictive power in predicting the progression of MCI to AD. Certain subregions of the volume correlated with cognitive scales. Conclusion: Subregions of the angular gyrus are essential in the early onset and subsequent development of AD, and early detection of the volume of these regions may be useful in identifying the tendency to develop the disease and its treatment.
Background: In neuroscience, Ca2+ imaging is a prevalent technique used to infer neuronal electrical activity, often relying on optical signals recorded at low sampling rates (3 to 30 Hz) across multiple neurons simultaneously. This study investigated whether increasing the sampling rate preserves critical information that may be missed at slower acquisition speeds. Methods: Primary neuronal cultures were prepared from the cortex of newborn pups. Neurons were loaded with Oregon Green BAPTA-1 AM (OGB1-AM) fluorescent indicator. Spontaneous neuronal activity was recorded at low (14 Hz) and high (500 Hz) sampling rates, and the same neurons (n = 269) were analyzed under both conditions. We compared optical signal amplitude, duration, and frequency. Results: Although recurring Ca2+ transients appeared visually similar at 14 Hz and 500 Hz, quantitative analysis revealed significantly faster rise times and shorter durations (half-widths) at the higher sampling rate. Small-amplitude Ca2+ transients, undetectable at 14 Hz, became evident at 500 Hz, particularly in the neuropil (putative dendrites and axons), but not in nearby cell bodies. Large Ca2+ transients exhibited greater amplitudes and faster temporal dynamics in dendrites compared with somas, potentially due to the higher surface-to-volume ratio of dendrites. In neurons bulk-loaded with OGB1-AM, cell nucleus-mediated signal distortions were observed in every neuron examined (n = 57). Specifically, two regions of interest (ROIs) on different segments of the same cell body displayed significantly different signal amplitudes and durations due to dye accumulation in the nucleus. Conclusions: Our findings reveal that Ca2+ signal undersampling leads to three types of information loss: (1) distortion of rise times and durations for large-amplitude transients, (2) failure to detect small-amplitude transients in cell bodies, and (3) omission of small-amplitude transients in the neuropil.
Background: Deficits in emotion recognition have been shown to be closely related to social-cognitive functioning in schizophrenic. This study aimed to investigate the event-related potential (ERP) characteristics of social perception in schizophrenia patients and to explore the neural mechanisms underlying these abnormal cognitive processes related to social perception. Methods: Participants included 33 schizophrenia patients and 35 healthy controls (HCs). All participants underwent electroencephalogram recording while completing the Emotion Intensity Recognition Task (EIRT). Behavioral data and ERP components were analyzed using repeated measures analysis of variance. Results: Schizophrenia patients had longer reaction times (RTs) to sad faces compared with disgusted faces, and had lower accuracy than the HCs. Additionally, schizophrenia patients had lower accuracy than the HCs for disgusted faces, surprised faces, angry faces, and fearful faces. Late Positive Potential (LPP) mean amplitudes of the HCs were larger than the schizophrenia patients for sad faces in the frontal lobe and central lobe. For happy faces, the HCs elicited larger LPP mean amplitudes than schizophrenia patients in the frontal lobe and central lobe. For surprised faces, the LPP mean amplitudes were higher in the HCs in the central lobe and parietal lobe than in schizophrenia patients. The HCs exhibited larger LPP mean amplitudes for angry faces in the frontal lobe, central lobe, and parietal lobe than in schizophrenia patients. For fearful faces, the HCs elicited a larger LPP mean amplitude than schizophrenia patients in the frontal lobe, central lobe, and parietal lobe. Conclusions: Schizophrenia patients present impaired social perception, and the observed ERP patterns provide valuable insights into the neural mechanisms underlying the EIRT results, highlighting the differences between HCs and schizophrenia patients. These findings underscore the potential of the EIRT as a biomarker for cognitive and emotional dysregulation in schizophrenia. Clinical Trial Registration: No: ChiCTR2300078149. Registered 29 November, 2023; https://www.chictr.org.cn/showproj.html?proj=211510.
Mitochondria are organelles of eukaryotic cells delimited by two membranes and cristae that consume oxygen to produce adenosine triphosphate (ATP), and are involved in the synthesis of vital metabolites, calcium homeostasis, and cell death mechanisms. Strikingly, normal mitochondria function as an integration center between multiple conditions that determine neural cell homeostasis, whereas lesions that lead to mitochondrial dysfunction can desynchronize cellular functions, thus contributing to the pathophysiology of traumatic brain injury (TBI). In addition, TBI leads to impaired coupling of the mitochondrial electron transport system with oxidative phosphorylation that provides most of the energy needed to maintain vital functions, ionic homeostasis, and membrane potentials. Furthermore, mitochondrial metabolism produces signaling molecules such as reactive oxygen species (ROS), regulating calcium levels and controlling the expression profile of intrinsic pro-apoptotic effectors influenced by TBI. Hence, the set of these functions is widely referred to as ‘mitochondrial function’, although the complexity of the relationship between such components limits such a definition. In this review, we present mitochondria as a therapeutic target, focus on TBI, and discuss aspects of mitochondrial structure and function.
Objective: To study the use of a dementia screening tool in our clinic cohort of adults with Down syndrome. Study Design: A retrospective chart review of patients with Down syndrome was conducted to follow the use of the Adaptive Behaviour Dementia Questionnaire (ABDQ) in a dementia screening protocol. The ABDQ results for patients aged 40 years and older at a Down syndrome specialty clinic program were assessed. Based on caregiver feedback, an ABDQ with modified instructions was piloted and the impact assessed. Results: As part of our clinic’s initiative to implement a new clinical protocol to screen for dementia, the ABDQ was completed by 47 caregivers of adults with Down syndrome, aged 39 years and above, from December, 2021 to April, 2023. Based on clinical impressions at the same timepoint, the ABDQ had a sensitivity of 0%, specificity of 97.4%, positive predictive value of 0%, and negative predictive value of 80.4%. Nine patients were deemed to have mild cognitive impairment and/or dementia by clinical impressions, but they did not identify as positive on the ABDQ. The Down syndrome clinic team modified the ABDQ in an effort to provide clearer language and increased sensitivity. The modified ABDQ showed a sensitivity of 0%, specificity of 93.8%, positive predictive value of 0% and negative predictive value of 75%. Conclusion: Neither the original ABDQ nor a modified version adequately identified patients with cognitive impairment and/or dementia within the Down syndrome clinical program. The inability to replicate findings from the initial ABDQ validation may be due to differences in setting and format.
The complicated neurological syndrome known as multiple sclerosis (MS) is typified by demyelination, inflammation, and neurodegeneration in the central nervous system (CNS). Managing this crippling illness requires an understanding of the complex interactions between neurophysiological systems, diagnostic techniques, and therapeutic methods. A complex series of processes, including immunological dysregulation, inflammation, and neurodegeneration, are involved in the pathogenesis of MS. Gene predisposition, autoreactive T cells, B cells, and cytokines are essential participants in the development of the disease. Demyelination interferes with the ability of the CNS to transmit signals, which can cause a variety of neurological symptoms, including impaired motor function, sensory deficiencies, and cognitive decline. Developing tailored therapeutics requires understanding the underlying processes guiding the course of the disease. Neuroimaging, laboratory testing, and clinical examination are all necessary for an accurate MS diagnosis. Evoked potentials and cerebrospinal fluid studies assist in verifying the diagnosis, but magnetic resonance imaging (MRI) is essential for identifying distinctive lesions in the CNS. Novel biomarkers have the potential to increase diagnostic precision and forecast prognosis. The goals of MS treatment options are to control symptoms, lower disease activity, and enhance quality of life. To stop relapses and reduce the course of the disease, disease-modifying treatments (DMTs) target several components of the immune response. DMTs that are now on the market include interferons, glatiramer acetate, monoclonal antibodies, and oral immunomodulators; each has a unique mode of action and safety profile. Symptomatic treatments improve patients' general well-being by addressing specific symptoms, including pain, sphincter disorders, fatigue, and spasticity. Novel treatment targets, neuroprotective tactics, and personalized medicine techniques will be the main focus of MS research in the future. Improving long-term outcomes for MS patients and optimizing disease treatment may be possible by utilizing immunology, genetics, and neuroimaging developments. This study concludes by highlighting the complexity of multiple MS, including its changing therapeutic landscape, diagnostic problems, and neurophysiological foundations. A thorough grasp of these elements is essential to improving our capacity to identify, manage, and eventually overcome this intricate neurological condition.
Introduction: The effects of remimazolam (Re) in combination with andrographolide (AP) on learning, memory, and motor abilities in rats following cardiopulmonary bypass (CPB) surgery were studied. Methods: We hypothesized that the combination of Re and AP could improve postoperative cognitive dysfunction (POCD) in rats after CPB by modulating nervous system inflammation. Cognitive function was assessed using the Morris Water Maze test, and the concentrations of tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) in serum were measured by enzyme-linked immunosorbent assay (ELISA). Apoptosis was evaluated using western blotting and the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining assay. Results: The results indicated that both Re and AP independently improved cognitive function in rats after CPB and inhibited the secretion of inflammatory factors and apoptosis in hippocampal tissues. Combined administration of Re and AP enhanced the alleviation of POCD compared with monotherapy. The adenosine monophosphate-activated protein kinase/silent information regulator of transcription 1 (AMPK/SIRT1) signaling pathway was activated by the combination of Re and AP. Conclusions: Collectively, the combination of Re and AP treatment significantly improves POCD in rats after CPB through activation of the AMPK/SIRT1 signaling pathway.
Background: Sports fatigue in soccer athletes has been shown to decrease neural activity, impairing cognitive function and negatively affecting motor performance. Transcranial direct current stimulation (tDCS) can alter cortical excitability, augment synaptic plasticity, and enhance cognitive function. However, its potential to ameliorate cognitive impairment during sports fatigue remains largely unexplored. This study investigated the effect of dual-site tDCS targeting the dorsolateral prefrontal cortex (DLPFC) or primary motor cortex (M1) on attention, decision-making, and working memory in elite soccer athletes during sports fatigue. Methods: Sports fatigue was induced in 23 (non-goalkeeper) elite soccer athletes, who then participated in three counterbalanced intervention sessions: dual-site tDCS over the M1, dual-site tDCS over the DLPFC, and sham tDCS. Following tDCS, participants completed the Stroop, Iowa Gambling, and 2-back tasks. Results: We found a significant improvement in Stroop task accuracy following dual-site anodal tDCS over the M1 compared with the sham intervention in the incongruent condition (p = 0.036). Net scores in the Iowa Gambling task during blocks 4 (p = 0.019) and 5 (p = 0.014) significantly decreased under dual-site tDCS targeting the DLPFC compared with the sham intervention. No differences in 2-back task performance were observed between sessions (all p > 0.05). Conclusions: We conclude that dual-site anodal tDCS applied to the M1 enhanced attention performance while tDCS targeting the DLPFC increased risk propensity in a decision-making task during sports fatigue in elite soccer athletes. However, dual-site anodal tDCS targeting either the M1 or DLPFC did not significantly influence working memory performance during sports fatigue in this population. These preliminary findings suggest that dual-site tDCS targeting the M1 has beneficial effects on attention performance, potentially informing future research on sports fatigue in athletes. Clinical Trial Registration: No: NCT06594978. Registered 09 September, 2024; https://clinicaltrials.gov/search?cond=NCT06594978.
Alzheimer’s disease (AD) is a common central neurodegenerative disease disorder characterized primarily by cognitive impairment and non-cognitive neuropsychiatric symptoms that significantly impact patients’ daily lives and behavioral functioning. The pathogenesis of AD remains unclear and current Western medicines treatment are purely symptomatic, with a singular pathway, limited efficacy, and substantial toxicity and side effects. In recent years, as research into AD has deepened, there has been a gradual increase in the exploration and application of medicinal plants for the treatment of AD. Numerous studies have shown that medicinal plants and their active ingredients can potentially mitigate AD by regulating various molecular mechanisms, including the production and aggregation of pathological proteins, oxidative stress, neuroinflammation, apoptosis, mitochondrial dysfunction, neurogenesis, neurotransmission, and the brain-gut microbiota axis. In this review, we analyzed the pathogenesis of AD and comprehensively summarized recent advancements in research on medicinal plants for the treatment of AD, along with their underlying mechanisms and clinical evidence. Ultimately, we aimed to provide a reference for further investigation into the specific mechanisms through which medicinal plants prevent and treat AD, as well as for the identification of efficacious active ingredients derived from medicinal plants.
Background: The significance of tactile stimulation in human social development and personal interaction is well documented; however, the underlying cerebral processes remain under-researched. This study employed functional magnetic resonance imaging (fMRI) to investigate the neural correlates of social touch processing, with a particular focus on the functional connectivity associated with the aftereffects of touch. Methods: A total of 27 experimental subjects were recruited for the study, all of whom underwent a 5-minute calf and foot massage prior to undergoing resting-state fMRI. Additionally, 11 healthy controls participated solely in the resting-state fMRI recording. A functional connectivity network analysis was conducted to examine the alterations in connections between different brain regions following massage. Results: The findings indicated the involvement of discrete neural networks in the processing of social touch, with notable discrepancies in functional connectivity observed between the experimental and control groups. The study revealed that the control group exhibited a higher degree of connectivity within a subnetwork comprising 25 connections and 23 nodes than the experimental group following the massage intervention. The experimental group showed hypoactivation in this subnetwork following the massage. The left anterior pulvinar thalamus and the right pregenual anterior cingulate cortex, which serve as the key hubs within this subnetwork, exhibited higher clustering and increased node strength in the control group. Relatively small and unequal sample sizes are the limitations of the study that may affect the generalizability of the results. Conclusions: These findings elucidate the neural underpinnings of tactile experiences and their potential impact on behavior and emotional state. Gaining insight into these mechanisms could inform therapeutic approaches that utilize touch to mitigate stress and enhance mental health. From a practical standpoint, our results have significant implications for the development of sensory stimulation strategies for patients with prolonged disorders of consciousness, sensory loss, autism spectrum disorders, or limited access to tactile interaction in their upper extremities.
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Background: Glioma is the most common malignancy in the central nervous system. Even with optimal therapies, glioblastoma (the most aggressive form of glioma) is incurable, with only 26.5% of patients having a 2-year survival rate. The present meta-analysis evaluated the association of magnetic resonance imaging (MRI)-derived parameters in glioma patients with progression-free survival (PFS) and overall survival. Eligible clinical articles on glioma patients included those that contained an evaluation of the association between MRI findings, PFS, and overall length of survival. Methods: Review of the literature included the following databases: WHO International Clinical Trials Registry Platform; Google Scholar; Web of Science; PubMed; SIGLE; NYAM; Scopus; Randomized controlled trial (RCT); Virtual Health Library (VHL); Cochrane Collaboration; EMBASE; and Clinical Trials. Results: The current review included 20 studies, and covered 2097 patients with gliomas. There were 1310 patients with glioblastoma and 320 with astrocytoma. There were 161 patients with grade-2 gliomas and 111 patients with grade-3. Tumour necrosis, peritumoural oedema, and multiple lesions were associated with PFS, as well as tumour necrosis and peritumoural oedema with overall survival. Conclusions: The present meta-analysis highlighted the ability of MRI to predict PFS and overall survival in patients with gliomas. This is crucial to identify patients at risk for poor survival outcomes and for individualising the treatment plan for such patients. The PROSPERO Registration: CRD42023489535, https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=489535.
Background: Observation, execution, and imitation of target actions based on mirror neuron network (MNN) have become common physiotherapy strategies. Electrical stimulation (ES) is a common intervention to improve muscle strength and motor control in rehabilitation treatments. It is possible to enhance MNN’s activation by combining motor execution (ME) and motor imitation (MI) with ES simultaneously. This study aims to reveal whether ES could impact cortical activation during ME and MI. Methods: We recruited healthy individuals and assigned them randomly to the control group (CG) or experiment group (EG). Participants in EG performed ME and MI tasks with ES, while participants in CG performed the same two tasks with sham ES. We utilized functional near-infrared spectroscopy (fNIRS) to detect brain activation of MNN during ME and MI with and without ES, a randomized block design experiment paradigm was designed. Descriptive analysis of oxy-hemoglobin (HbO) and deoxy-hemoglobin (HbR) were used to show the hemoglobin (Hb) concentration changes after different event onsets in both CG and EG, a linear mixed-effects model (LMM) of HbO data was employed to analyze the effect of ES on the activation of MNN. Results: A total of 102 healthy adults were recruited and 72 participants’ data were analysed in the final report. The block averaged Hb data showed that HbO concentration increased and HbR concentration decreased in most MNN regions during ME and MI in both groups. The LMM results showed that ES can significantly improve the activation of inferior frontal gyrus, middle frontal gyrus, and precentral gyrus during MI, the supplementary motor area, inferior parietal lobule, and superior temporal gyri showed increased activation, but without statistical significance. Although the results did not reach statistical significance during ME, ES still showed positive effects on increased overall activations. Conclusions: In this study, we present potential novel rehabilitation approaches that combines MNN strategies and low-frequency ES to enhance cortical activation. Our results revealed that ES has potential to increase activation of most MNN brain areas, providing evidence for related rehabilitative interventions and device development. Clinical Trial Registration: This study was registered on the China Clinical Trial Registration Center (identifier: ChiCTR2200064082, registered 26, September 2022, https://www.chictr.org.cn/showproj.html?proj=178285).
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Authors: Kim H.; Kim S.; Jun S.; Nam C.
Published: 2025/3
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AbstractSocial interaction plays a crucial role in human societies, encompassing complex dynamics among individuals. To understand social interaction at the neural level, researchers have utilized hyperscanning in several social settings. These studies have mainly focused on inter-brain synchrony and the efficiency of paired functional brain networks, examining group interactions in dyads. However, this approach may not fully capture the complexity of multiple interactions, potentially leading to gaps in understanding inter-network differences. To overcome this limitation, the present study aims to bridge this gap by introducing methodological enhancements using the multilayer network approach, which is tailored to extract features from multiple networks. We applied this strategy to analyze the triad condition during social behavior processes to identify group interaction indices. Additionally, to validate our methodology, we compared the multilayer networks of triad conditions with group synchrony to paired conditions without group synchrony, focusing on statistical differences between alpha and beta waves. Correlation analysis between inter-brain and group networks revealed that this methodology accurately reflects the characteristics of actual behavioral synchrony. The findings of our study suggest that measures of paired brain synchrony and group interaction may exhibit distinct trends, offering valuable insights into interpreting group synchrony.
Authors: Maier M.; Leonhardt A.; Blume F.; Bideau P.; Hellwich O.; Rahman R.
Published: 2025/3
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AbstractThe interplay of mind attribution and emotional responses is considered crucial in shaping human trust and acceptance of social robots. Understanding this interplay can help us create the right conditions for successful human-robot social interaction in alignment with societal goals. Our study shows that affective information about robots describing positive, negative or neutral behavior leads participants (N=90) to attribute mental states to robot faces, modulating impressions of trustworthiness, facial expression and intentionality. EEG recordings from 30 participants revealed that affective information influenced specific processing stages in the brain associated with early face perception (N170 component) and more elaborate stimulus evaluation (late positive potential, LPP). However, a modulation of fast emotional brain responses, typically found for human faces (early posterior negativity, EPN), was not observed. These findings suggest that neural processing of robot faces alternates between being perceived as mindless machines and intentional agents: people rapidly attribute mental states during perception, literally seeing good or bad intentions in robot faces, but are emotionally less affected than when facing humans. These nuanced insights into the fundamental psychological and neural processes underlying mind attribution can enhance our understanding of human-robot social interactions and inform policies surrounding the moral responsibility of artificial agents.
Authors: Roberge A.; Duncan J.; Fiset D.; Brisson B.
Published: 2025/2
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ABSTRACTApparent race of a face impacts processing efficiency, typically leading to an own-race advantage. For instance, own-race facial expressions are more accurately recognized, and their intensity better appraised, compared to other-race faces. Furthermore, these effects appear susceptible to implicit bias. Here, we aimed to better understand impacts of race and implicit racial bias on facial expression processing by looking at automatic and nonautomatic expression processing stages. To this end, scalp electroencephalography was recorded off a group of White participants while they completed a psychological refractory period dual-task paradigm in which they viewed neutral or fearful White (i.e., own-race) and Black (i.e., other-race) faces. Results showed that, irrespective of race, early perceptual expression processing indexed by the N170 event-related potential was independent of central attention resources and racial attitudes. On the other hand, later emotional content evaluation indexed by the late positive potential (LPP) was dependent on central resources. Furthermore, negative attitudes toward Black individuals amplified LPP emotional response to White (vs. Black) faces irrespective of central attention resources. Thus, it seems it is racial bias, more than race per se, that impacts facial expression processing, but this effect only manifests itself during later semantic processing of facial expression content.
Authors: Papantoni A.; Gearhardt A.; Yokum S.; Hoover L.; Finn E.; Shearrer G.; Smith Taillie L.; Shaikh S.; Meyer K.; Burger K.
Published: 2025/N/A
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AbstractFood advertisements target adolescents, contributing to weight gain and obesity. However, whether brain connectivity during those food advertisements can predict weight gain is unknown. Here, 121 adolescents [14.1 ± 1.0 years; 50.4% female; body mass index (BMI): 23.4 ± 4.8; 71.9% White] completed both a baseline fMRI paradigm viewing advertisements (unhealthy fast food, healthier fast food, and nonfood) and an anthropometric assessment 2 years later. We used connectome-based predictive modeling to derive brain networks that were associated with BMI both at baseline and the 2-year follow-up. During exposure to unhealthy fast-food commercials, we identified a brain network comprising high-degree nodes in the hippocampus, parahippocampal gyrus, and fusiform gyrus rich with connections to prefrontal and occipital nodes that predicted lower BMI at the 2-year follow-up (r = 0.17; P = .031). A similar network was derived from baseline BMI (n = 168; r = 0.34; P < .001). Functional connectivity networks during exposure to the healthier fast food (P = .152) and nonfood commercials (P = .117) were not significant predictors of 2-year BMI. Key brain regions in our derived networks have been previously shown to encode aspects of memory formation, visual processing, and self-control. As such, the integration of these regions may reflect a mechanism of adolescents’ ability to exert self-control toward obesogenic food stimuli.
Authors: Yu C.; Eggleston R.; Zhang K.; Nickerson N.; Sun X.; Marks R.; Hu X.; Brennan J.; Wellman H.; Kovelman I.
Published: 2025/N/A
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AbstractTheory of mind (ToM) refers to our understanding of people’s mental states. This ability develops in childhood and influences later social life. However, neuroimaging of ToM in young children often faces challenges in ecological validity and quality data collection. We developed and implemented an innovative naturalistic story-listening paradigm, which is child-friendly, engaging, and ecologically valid, to shed light on ToM neural mechanisms in childhood. Children (N = 51; age range = 6–12 years) listened to a chapter of Alice’s Adventures in Wonderland during functional near-infrared spectroscopy neuroimaging. Methodologically, we showed the feasibility and utility of our paradigm, which successfully captured the neural mechanisms of ToM in young children. Substantively, our findings confirm and extend previous results by revealing the same ToM brain regions found in the adult and adolescent literature, including, specifically, the activations of the right temporoparietal junction. We further confirm that ToM processing has its own specialized neural profile, different from the left frontal and temporal activations found during language processing, with the language being independent of, but potentially supportive, of ToM deployment and development.
Authors: Lian T.; Jiao Z.; Juan S.; Zhang P.
Published: 2025/N/A
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AbstractSocial pain is a common occurrence in interpersonal interactions, yet limited research has explored the neural mechanisms underlying both social pain and social pain empathy. Existing studies often focus on the neural processes of individuals experiencing pain, referred to as “subjects,” or those empathizing with them, known as “observers.” This study examines the neural mechanisms involved in the process of social pain empathy from the perspective of interpersonal brain synchronization (IBS). To do so, we employed functional near-infrared spectroscopy to simultaneously scan the brains of both subjects and observers in social pain scenarios created using the Cyberball paradigm. The study’s findings indicate that in social pain contexts, the IBS among dyads composed of subjects and observers was significantly enhanced in the dorsolateral prefrontal cortex compared to nonsocial pain contexts. This brain region is associated with emotion regulation. Furthermore, we found that this enhancement depended on the observers’ levels of rejection sensitivity. This study provides the inaugural exploration into the neural mechanisms underlying social pain empathy through the lens of IBS.
Authors: Kroczek L.; Mühlberger A.
Published: 2025/N/A
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AbstractFacial emotional expressions are crucial in face-to-face social interactions, and recent findings have highlighted their interactive nature. However, the underlying neural mechanisms remain unclear. This electroencephalography study investigated whether the interactive exchange of facial expressions modulates socio-emotional processing. Participants (N = 41) displayed a facial emotional expression (angry, neutral, or happy) toward a virtual agent, and the agent then responded with a further emotional expression (angry or happy) or remained neutral (control condition). We assessed subjective experience (valence, arousal), facial EMG (Zygomaticus, Corrugator), and event-related potentials (EPN, LPP) elicited by the agent’s response. Replicating previous findings, we found that an agent’s happy facial expression was experienced as more pleasant and elicited increased Zygomaticus activity when participants had initiated the interaction with a happy compared to an angry expression. At the neural level, angry expressions resulted in a greater LPP than happy expressions, but only when participants directed an angry or happy, but not a neutral, expression at the agent. These findings suggest that sending an emotional expression increases salience and enhances the processing of received emotional expressions, indicating that an interactive setting alters brain responses to social stimuli.
Authors: Li W.; Wei Z.; Wu J.; Song R.; Liu J.; Cui F.
Published: 2025/N/A
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AbstractEmpathy for social pain encompasses both affective and cognitive responses to others’ emotional reactions following negative social encounters, facilitating an understanding of their suffering and promoting prosocial behaviors. This study examined how a scarcity mindset affects empathy for social pain and prosocial intentions at behavioral and neural levels. Sixty participants were randomly assigned to either the scarcity or abundance mindset group. They viewed images of social exclusion or neutral scenarios and subsequently rated the perceived unpleasantness of the target person and their willingness to provide comfort during a stage-game paradigm. The results showed that participants in the scarcity mindset group demonstrated greater differentiation in their ratings of unpleasantness and willingness to comfort when exposed to social exclusion images compared to neutral ones, relative to the abundance mindset group. Electrophysiological data revealed that social exclusion images elicited larger late positive potential (LPP) amplitudes in the scarcity mindset group, but not in the abundance mindset group. Additionally, within the scarcity mindset group, affective empathy trait scores moderated the relationship between LPP amplitudes and willingness to comfort ratings. These findings highlight the amplifying effects of a scarcity mindset on empathy for social pain and prosocial intentions, and emphasize the role of affective empathy traits in this dynamic process.
Authors: Lu J.; Riecke L.; Ryan B.; de Gelder B.
Published: 2025/N/A
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AbstractThis study used electroencephalography (EEG) and personalized avatars to investigate the neural mechanisms underlying personal identity perception. Compound avatar images combining participants’ own faces and bodies, as well as those of others, were generated from photographs. Participants underwent an embodiment training for each avatar type in a virtual reality environment, where they controlled the avatar’s actions during physical exercise tasks. Subjective assessments by participants confirmed a stronger identification with avatars representing their own identity compared to those representing others. Analysis of event-related potentials (ERPs) evoked by viewing the avatar revealed that avatars representing the participants’ self-identity elicited weaker N2 and P1 responses compared to avatars representing other identities. No significant effects on N170 responses were observed. Control conditions utilizing avatars with modified body characteristics confirmed that the reduction in N2 amplitude was specifically related to identity perception rather than variations in visual body size. These findings suggest that the perception of self-identity occurs rapidly, within ∼200 ms, indicating the integration of visual face and body information into identity representation at an early stage.
Authors: Yang C.; Guo Z.; Cheng L.
Published: 2025/N/A
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AbstractOxytocin (OT), a neuropeptide pivotal in social and reproductive behaviors, has recently gained attention for its potential impact on cognitive processes relevant to creativity. Yet, the direct intricate interplay between OT and creativity, particularly in the context of individual differences in motivational orientations, remains poorly understood. Here, we investigated the effects of intranasal OT on creative thinking in individuals characterized by varying levels of approach and avoidance motivations. The initial study, involving participants with high approach or avoidance motivation, employed the Alternative Uses Task to assess creativity under OT administration. Subsequently, the second study induced different motivational states through a recall task, aiming to validate and extend observed effects. Results revealed a significant enhancement of creativity in individuals with approach motivation following OT administration, while no parallel effect was discerned in those with avoidance motivation. Aligning with behavioral findings, functional connectivity and graph theory analyses of neural data illuminated the coordinated effects of OT on creativity-related neural networks. These outcomes collectively suggest that OT exerts a dissociable influence on creativity contingent upon an individual’s motivational tendencies, providing insights into the intricate relationship between OT and human creative behavior.
Authors: Emadi Andani M.; Braga M.; Da Dalt F.; Piedimonte A.; Carlino E.; Fiorio M.
Published: 2025/N/A
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AbstractThe aim of this study is to investigate whether expectancy, induced through a placebo procedure, favors the activation of the corticospinal tract before movement initiation. By adopting the premovement facilitation paradigm, we applied transcranial magnetic stimulation over the left or right primary motor cortex at rest and 100 ms or 50 ms before movement onset while healthy volunteers performed a reaction time (RT) motor task consisting of abductions of the right or left thumb after a go signal. Participants in the placebo group received an inert electrical device applied on the right forearm along with information on its speed-enhancing properties. A control group received the same device with overt information about its inert nature, while another control group underwent no intervention. Along with RT, we measured the amplitude of the motor evoked potential (MEP) before and after the procedure. Compared to the control groups, the placebo group had faster RT and greater MEP amplitude before movement initiation. This study demonstrates that the placebo effect can boost the activity of the corticospinal tract before movement onset, and this modulation positively impacts motor performance. These results give experimental support to the active inference account.
Authors: Grande L.; Xie Y.; Zagoory-Sharon O.; Watamura S.; Yeh T.; Feldman R.; Kim P.
Published: 2025/N/A
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AbstractIndividuals who perceive the caregiving they received from their parents as more caring tend to bond better with their infants and show more sensitive parenting behaviors. Early caregiving experiences are also related to differences in the functions of hormonal systems, including the oxytocinergic system. The current study examined how perceptions of childhood maternal care relate to parenting behaviors, oxytocin levels, and neural responses to infant stimuli. Perceived childhood maternal care was measured using the Parental Bonding Instrument (PBI) for 54 first-time birthing parents. Salivary oxytocin and observations of parenting behaviors were assessed during parent–infant play at 3.5 months postpartum. Neural activation while listening to infant cry was measured with fMRI. More positive perceptions of childhood maternal care and higher oxytocin were interactively related to greater anterior cingulate activation to own infant’s cry. Higher oxytocin levels were associated with reduced left cuneus activation in response to own infant’s cry when compared with control cry and matched noise. Findings suggested that positive memories of childhood caregiving may have protective functions for birthing parents with high oxytocin levels during the early postpartum period, a time when parents need to manage increased stress and form an exclusive bond with their baby.
Authors: Hughes G.; Gooding P.
Published: 2025/N/A
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AbstractIn the Ouija board phenomenon, the lack of agency experienced by the players leads them to attribute the movement of the planchette to spirits. The aim of this study was to investigate the neural and cognitive mechanisms involved in generating the sense of agency in such a joint action context. Two players (a participant and a confederate) jointly moved a Ouija board-style planchette containing a wireless mouse. This, in turn, moved a digital board on the screen. Participants reported a greater sense of agency in the condition where they had complete control of the planchette (the ‘self’ condition), and least agency when they passively held the planchette while it was moved by the confederate (‘other’ condition), with the two ‘joint’ action conditions in between. While the N1 peak did not differ between conditions, the early part of the N1 differentiated between the joint action conditions, and the solo action conditions. In contrast, the Tb and P2 components differed between the ‘other’ condition and the ‘self’ and ‘joint’ conditions. These findings are discussed with reference to motor-prediction and attentional mechanisms.
Authors: Huang C.; Zhou Z.; Angus D.; Sedikides C.; Kelley N.
Published: 2025/N/A
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AbstractThe reward responsivity hypothesis of self-control proposes that irrespective of self-control success, exercising self-control is aversive and engenders negative affect. To countermand this discomfort, reward-seeking behavior may be amplified after bouts of self-control, bringing individuals back to a mildly positive baseline state. Previous studies indicated that effort—an integral component of self-control—can increase reward responsivity. We sought to test and extend the reward responsivity hypothesis by asking if exercising self-control increases a neural marker of reward responsivity [Reward Positivity (RewP)] differentially for hedonic rewards or eudaimonic rewards. We instructed participants (N = 114) to complete a speeded reaction time task where they exercised self-control (incongruent Stroop trials) or not (congruent Stroop trials) and then had the opportunity to win money for themselves (hedonic rewards) or a charity (eudaimonic rewards) while electroencephalography was recorded. Consistent with the reward responsivity hypothesis, participants evinced a larger RewP after exercising self-control (vs. not exercising self-control). Participants also showed a larger RewP for hedonic over eudaimonic rewards. Self-control and reward type did not interactively modulate RewP, suggesting that self-control increases reward responsivity in a domain-general manner. The findings provide a neurophysiological mechanism for the reward responsivity hypothesis of self-control and promise to revitalize the relevant literature.
Authors: Lin H.; Liang J.
Published: 2025/N/A
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AbstractLittle is known about the effect of prior social performance feedback on face processing. Our previous study explored how equal and unequal social comparison-related outcomes modulate event-related potential (ERP) responses to subsequently presented faces, where interests between oneself and others were independent (noncompetitive situations). Here, we aimed to extend this investigation by assessing how different unequal social comparison-related outcomes affect face processing under noncompetitive and competitive situations (i.e. a conflict of interest exists between the self and others). To address this issue, 39 participants were exposed to self-related and social comparison-related outcomes, categorized as positive or negative, after performing an attentional task with peers. Rewards and punishments depended on social comparison-related outcomes in the competition condition and on self-related outcomes in the noncompetition condition. ERP results showed that social comparison-related outcomes influenced P100 responses to faces in the self-positive condition. More notably, the effects on N170 responses observed in the noncompetition condition were absent in the competition condition. There was an effect on late positive potential responses only in the competition and self-negative condition. These findings suggest that social comparison-related outcomes influence early face processing irrespective of competition, while competition subsequently disrupts this processing but, later, enhances depending on self-related outcomes.
Authors: Acuña A.; Morales S.; Uriarte-Gaspari L.; Aguirre N.; Brandani A.; Huart N.; Mattos J.; Pérez A.; Cuña E.; Waiter G.; Steele D.; Armony J.; García-Fontes M.; Cabana Á.; Gradin V.
Published: 2025/N/A
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AbstractSocial comparisons are a core feature of human life. Theories posit that social comparisons play a critical role in depression and social anxiety triggering negative evaluations about the self, as well as negative emotions. We investigated the neural basis of social comparisons in participants with major depression and/or social anxiety (MD-SA, n = 56) and healthy controls (n = 47) using functional magnetic resonance imaging. While being scanned participants performed a social comparison task, during which they received feedback about their performance and the performance of a coplayer. Upward social comparisons (being worse than the coplayer) elicited high levels of negative emotions (shame, guilt, and nervousness) across participants, with this effect being enhanced in the MD-SA group. Notably, during upward comparison the MD-SA group showed greater activation than the control group in regions of the default mode network (DMN). Specifically, for upward comparison MD-SA participants demonstrated increased activation in the dorsomedial prefrontal cortex and reduced deactivation in the posteromedial cortex, regions linked to self-referential processing, inferences about other people’s thoughts, and rumination. Findings suggest that people with depression and social anxiety react to upward comparisons with a more negative emotional response, which may be linked to introspective processes related to the DMN.
Authors: Di Tella S.; Zinzi P.; Anzuino I.; Lo Monaco M.; Tondinelli A.; Magistri M.; Petracca M.; Solito M.; Calabresi P.; Bentivoglio A.; Silveri M.
Published: 2025/N/A
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AbstractTheory of Mind (ToM) is the ability to predict the behaviour of others by inferring their cognitive and affective states. The literature suggests that different neural substrates within the basal ganglia are involved in the affective (ventral striatum) and cognitive (dorsal striatum) components of ToM. We investigated ToM dysfunction in two different basal ganglia pathologies, Huntington’s disease (HD) and Parkinson’s disease (PD), in their early stages. Indeed, a different progression of neurodegeneration from the dorsal striatum to the ventral striatum is described in the two diseases. We also investigated whether there is a correlation between ToM and executive function. Twenty-one patients with HD, 21 with PD, and 22 healthy subjects (HS) were recruited. All participants completed a ToM assessment using the Yoni task, which assesses both cognitive and affective components at two levels of meta-representational difficulty (i.e. first-order items only require inferring the mental state of a person, while second-order items also require inferring the mental states of a person about others). The clinical groups also underwent a full neuropsychological assessment. In HD patients, both cognitive and affective ToM were equally impaired, whereas in PD patients, impairment of the cognitive component predominated. Specifically, compared to HS, HD patients scored lower on both inferential levels and on both cognitive and affective components, whereas PD patients scored lower than HS only on second-order and cognitive items. In the clinical groups, there was an imbalance between the cognitive and affective components, with higher accuracy on affective items. Performance on the Yoni task did not correlate with tests assessing executive functions. We suggest that the different pattern of ToM alteration in HD and PD may be a result of differential involvement of the ventral and dorsal striatum and that ToM abilities in these clinical populations are not directly supported by executive functioning.
Authors: Rilling J.; Lee M.; Zhou C.; Hepburn K.; Perkins M.; Gaser C.
Published: 2025/N/A
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AbstractMiddle-aged adults who are parents have better average cognitive performance and lower average brain age compared with middle-aged adults without children, raising the possibility that caregiving slows brain aging. Here, we investigate this hypothesis in two additional groups of caregivers: grandmothers and caregivers for people living with dementia (PLWD). Demographic, questionnaire, and structural Magnetic Resonance Imaging (MRI) data were acquired from n = 50 grandmothers, n = 24 caregivers of PLWD, and n = 37 non-caregiver controls, and BrainAGE was estimated. BrainAGE estimation results suggest that after controlling for relevant covariates, grandmothers had a brain age that was 5.5 years younger than non-grandmother controls, and caregivers of PLWD had brains that were 4.7 years younger than non-caregiver controls. Women who became grandmothers at a later age had lower brain age than those who became grandmothers at an earlier age. Among caregivers of PLWD, stress and caregiving burden were associated with increased brain age, such that the beneficial effect of caregiving on brain age was reduced in caregivers reporting more burden. Our findings suggest that caring for dependents may slow brain aging.
Authors: Pruitt P.; Yu K.; Lahna D.; Schwartz D.; Peltier S.; Silbert L.; Dodge H.
Published: 2025/N/A
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AbstractDespite having a meaningful impact on the quality of life, emotional well-being is often understudied in older adults in favor of cognitive performance, particularly when examining its association with neurobiological function. Socially isolated older adults have poorer emotional health than their non-isolated peers and are at increased risk of dementia. Characterizing neurobiological correlates of emotional characteristics in this population may help elucidate pathways that link social isolation and dementia risk. In a sample of 50 socially isolated older adults aged 75+ years (“older-old”; 30 with mild cognitive impairment; 20 with unimpaired cognition), we use the National Institutes of Health Toolbox—Emotion Battery to examine associations between emotional characteristics and functional magnetic resonance imaging (fMRI)-derived intrinsic brain network functional connectivity. We found a positive association between the default mode network connectivity and negative affect. Amygdala–ventromedial prefrontal cortex (vmPFC) connectivity was negatively associated with psychological well-being and positively associated with negative affect. These results did not survive correction for multiple comparisons. These findings replicate, in a sample of socially isolated older-old adults, the previous work highlighting the relationship between amygdala–vmPFC connectivity and individual differences in emotional health, with more inverse connectivity associated with better emotional characteristics.
Authors: Haihambo N.; Baetens K.; Deroost N.; Baeken C.; Van Overwalle F.
Published: 2025/N/A
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AbstractThis dynamic causal modeling (DCM) analysis, comprising 99 participants from 4 studies, investigated effective neuronal connectivity during social action sequence prediction. The analysis focused on mentalizing areas within the cerebellum, specifically the bilateral Crus 1, Crus 2, and lobule IX, as well as cerebral mentalizing areas within the precuneus, temporo-parietal junction (TPJ), and dorsal medial prefrontal cortex (dmPFC). Consistent with previous research, we found robust bidirectional closed loop connections between the posterior cerebellar Crus and cerebral mentalizing areas. We also found previously unexplored unidirectional connections originating from cerebellar lobule IX to the dmPFC and left TPJ and from the right TPJ to lobule IX. Furthermore, we uncovered many bidirectional closed loops within the cerebellum between the left and right Crus 1, and between Crus 1 and Crus 2, and for the first time, between the bilateral Crus 2 and lobule IX. Our findings illuminate the distinct role of cerebellar Crus and lobule IX, and cerebral mentalizing areas in predicting social action sequences.
Authors: Keck J.; Bachmann J.; Zabicki A.; Munzert J.; Krüger B.
Published: 2025/N/A
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AbstractHumans are highly adept at inferring emotional states from body movements in social interactions. Nonetheless, it is under debate how this process is facilitated by neural activations across multiple brain regions. The specific contributions of various brain areas to the perception of valence in biological motion remain poorly understood, particularly those within the action observation network (AON) and those involved in processing emotional valence. This study explores which cortical regions involved in processing emotional body language depicted by kinematic stimuli contain valence information, and whether this is reflected either in the magnitude of activation or in distinct activation patterns. Results showed that neural patterns within the AON, notably the inferior parietal lobule (IPL), exhibit a neural geometry that reflects the valence impressions of the observed stimuli. However, the representational geometry of valence-sensitive areas mirrors these impressions to a lesser degree. Our findings also reveal that the activation magnitude in both AON and valence-sensitive regions does not correlate with the perceived valence of emotional interactions. Results underscore the critical role of the AON, particularly the IPL, in interpreting the valence of emotional interactions, indicating its essential function in the perception of valence, especially when observing biological movements.
Authors: Veranic K.; Ewing L.; Sambrook T.; Watson E.; Zhao M.; Bayliss A.
Published: 2025/N/A
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AbstractInterpersonal space is regulated carefully and updated dynamically during social interactions to maintain comfort. We investigated the naturalistic processing of interpersonal distance in real time and space using a powerful implicit neurophysiological measure of attentional engagement. In a sample of 37 young adults recruited at a UK university, we found greater EEG alpha band suppression when a person ‘occupies’ or‘moves into’ near-personal space than for a person occupying or moving into public space. In the dynamic condition only, the differences attenuated over the course of the experiment, and were sensitive to individual differences in social anxiety. These data show, for the first time, neurophysiological correlates of interpersonal distance coding in a naturalistic setting. Critically, while veridical distance is important for attentional response to the presence of a person in one’s space, the behavioural relevance of their movement through public and personal space takes primacy.
Authors: Gao T.; Zhou Y.; Pan X.; Li W.; Han S.
Published: 2025/N/A
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AbstractPrevious findings of better behavioral responses to self- over other-related stimuli suggest prioritized cognitive processes of self-related information. However, it is unclear whether the processing of information related to important others (e.g.friends) may be prioritized over that related to the self in certain subpopulations and, if yes, whether friend-prioritization and self-prioritization engage distinct cognitive and neural mechanisms. We collected behavioral and electroencephalography (EEG) data from a large sample (N = 1006) during learning associations between shapes and person labels (self or a friend). Analyses of response times and sensitivities revealed two subpopulations who performed better to friend–shape or self–shape associations, respectively (N = 216 for each group). Drift diffusion model (DDM) analyses unraveled faster information acquisition for friend–shape (vs. self–shape) associations in the friend-prioritization group but an opposite pattern in the self-prioritization group. Trial-by-trial regression analyses of EEG data showed that the greater amplitudes of a frontal/central activity at 180–240 ms poststimulus were correlated with faster information acquisition from friend–shape associations in the friend-prioritization group but from self-shape associations in the self-prioritization group. However, the frontal/central neural oscillations at 8–18 Hz during perceptual learning were specifically associated with speed of information acquisition from friend–shape associations in the friend–prioritization-group. Our findings provide evidence for friend-prioritization in perceptual learning in a subpopulation of adults and clarify the underlying cognitive and neural mechanisms.
Authors: None
Published: 2025/N/A
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Authors: Cahart M.; Giampietro V.; O’Daly O.
Published: 2025/N/A
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AbstractEmotion studies have commonly reported atypical emotional processing in clinically depressed adolescents in the context of short-lasting emotional cues. However, interindividual differences in the moment-to-moment brain network dynamics that underlie this impaired emotional reactivity remain unclear, and the use of poorly matched controls and relatively small sample sizes represents major limitations in most neuroimaging depression studies to date. Here, we address these concerns by using the temporal features of a rich naturalistic paradigm (i.e. a clip from the movie ‘Despicable Me’) to investigate brain network dynamics in 42 clinically depressed and 42 nondepressed adolescents aged 16–21 years, matched for age, gender, and psychiatric comorbidities. Using a dynamics functional connectivity analysis technique called Leading Eigenvector Dynamics Analysis, we found that the clinical group exhibited significantly higher probability of occurrence of the dorsal attention network and lower recruitment of the fronto-parietal, default mode network, ventral attention, and somato-motor networks throughout the task. This brain/behaviour relationship was prominent during less emotional moments of the movie, consistent with previous findings. Our findings demonstrate the key role of continuous affective measures in providing information about how activity in the depressed brain evolves as emotional intensity unfolds throughout the movie. Future studies with a larger sample size are needed in order to corroborate the present findings.
Authors: Amoruso L.; Moguilner S.; Castillo E.; Kleineschay T.; Geng S.; Ibáñez A.; García A.
Published: 2024/12
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AbstractHuman vocabularies include specific words to communicate interpersonal behaviors, a core linguistic function mainly afforded by social verbs (SVs). This skill has been proposed to engage dedicated systems subserving social knowledge. Yet, neurocognitive evidence is scarce, and no study has examined spectro-temporal and spatial signatures of SV access. Here, we combined magnetoencephalography and time-resolved decoding methods to characterize the neural dynamics underpinning SVs, relative to nonsocial verbs (nSVs), via a lexical decision task. Time-frequency analysis revealed stronger beta (20 Hz) power decreases for SVs in right fronto-temporal sensors at early stages. Time-resolved decoding showed that beta oscillations significantly discriminated SVs and nSVs between 180 and 230 ms. Sources of this effect were traced to the right anterior superior temporal gyrus (a key hub underpinning social conceptual knowledge) as well as parietal, pre/motor and prefrontal cortices supporting nonverbal social cognition. Finally, representational similarity analyses showed that the observed fronto-temporal neural patterns were specifically predicted by verbs’ socialness, as opposed to other psycholinguistic dimensions such as sensorimotor content, emotional valence, arousal, and concreteness. Overall, verbal conveyance of socialness seems to involve distinct neurolinguistic patterns, partly shared by more general sociocognitive and lexicosemantic processes.
Authors: Mąka S.; Wiśniewska M.; Piejka A.; Chrustowicz M.; Okruszek Ł.
Published: 2024/12
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AbstractDespite theoretical emphasis on loneliness affecting social information processing, empirical studies lack consensus. We previously adopted a clinical science framework to measure the association between social cognitive capacity and bias and both objective and perceived social isolation in nonclinical participants. Our prior study found that while objective social isolation is linked to both social cognitive capacity and social cognitive bias, loneliness is associated only with the latter. This study extended our previous model using a computational approach to capture implicit cognitive processes. We replicated and extended our earlier findings with a new sample of 271 participants, using neuropsychological tasks and a dot-probe paradigm that was analyzed via Drift Diffusion Model. We presented two complementary trajectories of how social cognitive bias may arise: the increased propensity to engage with salient social stimuli or a decreased information processing capacity dependent on the presence or absence of potential social threats. Furthermore, we found evidence that loneliness is associated with the time needed for perceptual processing of stimuli, both directly and indirectly, via social cognitive bias. Taken together, the complex and context-dependent nature of information processing biases observed in the current study suggests that complex and multifaceted interventions should be implemented to counter social information processing biases in lonely individuals.
Authors: Aslanidou A.; Andreatta M.; Wong A.; Wieser M.
Published: 2024/12
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AbstractFear of threatening contexts often generalizes to similar safe contexts, but few studies have investigated how contextual information influences cue generalization. In this study, we explored whether fear responses to cues would generalize more broadly in a threatening compared to a safe context. Forty-seven participants underwent a differential cue-in-context conditioning protocol followed by a generalization test, while we recorded psychophysiological and subjective responses. Two faces appeared on a computer screen in two contexts. One face (CS+) in the threat context (CTX+) was followed by a female scream 80% of the time, while another face (CS−) was not reinforced. No faces were reinforced in the safe context (CTX−). In the generalization test, the CSs and four morphs varying in similarity with the CS+ were presented in both contexts. During acquisition, conditioned responses to the cues were registered for all measures and the differential responding between CS+ and CS− was higher in CTX+ for US-expectancy ratings and skin conductance responses, but the affective ratings and steady-state visual evoked potentials were not context-sensitive. During test, adaptive generalized responses were evident for all measures. Despite increased US-expectancy ratings in CTX+, participants exhibited similar cue generalization in both contexts, suggesting that threatening contexts do not influence cue generalization.
Authors: Oboshi Y.; Iwabuchi T.; Takata Y.; Bunai T.; Ouchi Y.
Published: 2024/12
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AbstractAs a tactic to regulate emotions, distancing involves changing perspectives to alter the psychological distance from stimuli that elicit emotional reactions. Using magnetic resonance spectroscopy and functional magnetic resonance imaging, this study aimed to examine (i) whether the neural correlates of emotion upregulation via distancing differ across emotional valence (i.e. emotional responses toward positive and negative pictures), and (ii) whether the gamma-aminobutyric acid (GABA) concentration in the medial prefrontal cortex (MPFC), one of the crucial areas of emotion regulation, is correlated with brain activity related to either negative or positive emotion upregulation. Thirty-four healthy Japanese adults participated in this study. Compared to the condition involving positive emotion upregulation, negative emotion upregulation induced increased activation in the MPFC, left temporoparietal junction, bilateral anterior insula, pre-supplementary motor area, and bilateral cerebellum. In contrast, when comparing positive emotion upregulation with negative emotion upregulation, no significant activation was found. Right cerebellar activity during negative emotion upregulation was positively correlated with GABA concentration in the MPFC. These findings provide evidence of cerebellar involvement in the upregulation of negative emotion via distancing and its association with the prefrontal GABA concentration.
Authors: Tricoche L.; d’Halluin M.; Meunier M.; Pélisson D.
Published: 2024/11
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AbstractSocial Facilitation/Inhibition (SFI) refers to how others’ presence influences task performance positively or negatively. Our previous study revealed that peer presence modulated saccadic eye movements, a fundamental sensorimotor activity. Pro- and anti-saccades were either facilitated or inhibited depending on trial block complexity (Tricoche et al., 2020). In the present fMRI study, we adapted our paradigm to investigate the neural basis of SFI on saccades. Considering inter- and intra-individual variabilities, we evaluated the shared and distinct neural patterns between social facilitation and inhibition. We predicted an involvement of the saccade-related and attention networks, alongside the Theory-of-Mind (ToM) network, with opposite activity changes between facilitation and inhibition. Results confirmed peer presence modulation in fronto-parietal areas related to saccades and attention, in opposite directions for facilitation and inhibition. Additionally, the ventral attention network was modulated during inhibition. Default mode regions, including ToM areas, were also modulated. Finally, pupil size, often linked to arousal, increased with peers and correlated with dorsal attention regions and anterior insula activities. These results suggest that SFI engages task-specific and domain-general networks, modulated differently based on observed social effect. Attention network seemed to play a central role at both basic (linked to arousal or vigilance) and cognitive control levels.